Title of Invention	"A COMPOSITION COMPRISING A DOUBLE STRANDED RIBONUCLEIC ACID (DSRNA) AND DELIVERY ENHANCING PEPTIDES"
Abstract	The present invention relates to a composition comprising a double stranded ribonucleic acid (dsRNA) and a delivery enhancing peptide, wherein the dsRNA comprises an antisense strand that is complementary to a tumor necrosis factor-α (TNF-α) mRNA that comprises a nucleic acid sequence of CCGACUCAGCGCUGAGAUCAA (SEQ ID NO: 132)

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OF TREATING AN INFLAMMATORY DISEASE BY DOUBLE STRANDED RIBONUCLEIC The invention relates to methods and compositions for delivering nucleic acids into cells. More specifically, the invention relates to procedures and preparations for delivering double-stranded polynucleotides into cells to modify expression of target genes to alter a phenotype, such as a disease state or potential, of the cells. A central role of tumor necrosis factor (TNF-a) has been identified or implicated in the initiation and/or persistence of the inflammatory process(es) leading to a variety of diseases. These include rheumatoid arthritis (RA), Crohn's disease (CD), psoriasis, ankylosing spondylitis, Still's disease, polymyositis and dematomyositis, and vasculitis (including Behcet's disease and Wegener's granulomatosis) (Lorenz and Kalden (2002) Arthritis Research 4(suppl 3):S17-24). TNF-a production by adipose tissue has also been implicated in diabetes and obesity (Ruan and Lodish (2003) Cytokine Growth Factor Rev. 14:447-55). Limitations of established therapies (including methotrexate) have led to identification of certain inflammatory mediators as therapeutic targets for alternative therapies. In this connection novel therapeutic agents have been developed that are currently being testing, including monoclonal antibodies, cytokine receptor-human Ig constructs, and recombinant human proteins. There continues to be an unmet demand for effective therapeutic modalities for treating this class of diseases. Various stimuli are known to induce TNF-a production, including endotoxin, tumor cells, several viruses (including HIV), other cytokines, and various stress related responses. An animal model has been developed for nonclinical studies that were accepted by the U.S. Food and Drug Administration (FDA) as providing support for labeling of Remicade® for treatment of Crohn's Disease patients. The murine model (Tg 197, Tg211 and Tg5453 mice) came from the development of transgenic mice that constitutively express human TNF-a (Georgopoulos et al. (1996) J. Inflammation 46:86-97). Several other anti-TNF-a antibody therapies successfully applied this animal model to assess potency and prove efficacy (HUMIRA™, Infliximab, Adalimunab, Etanercept, Abgenix ABX10131). Delivering nucleic acids into animal and plant cells has long been an important object of molecular biology research and development. Recent developments in the areas of gene therapy, antisense therapy and RNA interference (RNAi) therapy have created a need to develop more efficient means for introducing nucleic acids into cells, A diverse array of plasmids and other nucleic acid "vectors" have been developed for delivering large polynucleotide molecules into cells. Typically these vectors incorporate large DNA molecules comprising intact genes for the purpose of transforming target cells to express a gene of scientific or therapeutic interest. The process by which exogenous nucleic acids are delivered artificially into cells is generally referred to as transfection. Cells can be transfected to uptake a functional nucleic acid from an exogenous source using a variety of techniques and materials. The most commonly used transfection methods are calcium phosphate transfection, and electroporation. A variety of other methods for tranducing cells to deliver exogenous DNA or RNA molecules have been developed, including viral-mediated transduction, cationic lipid or liposomal delivery, and numerous methods that target mechanical or biochemical membrane disruption/penetration (e.g., using detergents, microinjection, or particle guns). RNA interference is a process of sequence-specific post transcriptional gene silencing in cells initiated by a double-stranded (ds) polynucleotide, usually a dsRNA, that is homologous in sequence to a portion of a targeted messenger RNA (mRNA). Introduction of a suitable dsRNA into cells leads to destruction of endogenous, cognate mRNAs (i.e., mRNAs that share substantial sequence identity with the introduced dsRNA). The dsRNA molecules are cleaved by an RNase III family nuclease called dicer into short-interfering RNAs (siRNAs), which are 19-23 nucleotides (nt) in length. The siRNAs are then incorporated into a multicomponent nuclease complex known as the RNA-induced silencing complex or "RISC". The RISC identifies mRNA substrates through their homology to the siRNA, and effectuates silencing of gene expression by binding to and destroying the targeted mRNA. RNA interference is emerging a promising technology for modifying expression of specific genes in plant and animal cells, and is therefore expected to provide useful tools to treat a wide range of diseases and disorders amenable to treatment by modification of endogenous gene expression. There remains a long-standing need in the art for better tools and methods to deliver siRNAs and other small miiibitory nucleic acids (siNAs) into cells, particularly in view of the fact that existing techniques for delivering nucleic acids to cells are limited by poor efficiency and/or high toxicity of the delivery reagents. Related needs exist for improved methods and formulations to deliver siNAs in an effective amount, in an active and enduring state, and using non-toxic delivery vehicles, to selected cells, tissues, or compartments to mediate regulation of gene expression in a manner that will alter a phenotype or disease state of the targeted cells. SUMMARY OF THE INVENTION One aspect of the invention is the use of a formulation comprising double stranded ribonucleic acid (dsRNA) in the manufacture of a medicament for treating an inflammatory disease in a mammal and inhibiting production of tumor necrosis factor-a (TNF-a) in the mammal. Preferably, the inflammatory disease is a systemic disease. Most prefereably, the inflammatory disease is rheumatoid arthritis. In an embodiment of the invention, the formulation is administered to the circulation of the mammal, preferably intravenously. In another embodiment, the siRNA is delivered to blood leucocytes, preferably monocytes. In another embodiment, administration of the formulation decreases the levels of TNF-a in the circulation of the mammal. In a preferered embodiment the mammal is a human. Another aspect of the invention is a pharmaceutical formulation for treating an inflammatory disease in a mammal comprising double stranded ribonucleic acid (dsRNA), wherein the dsRNA is capable of modifying expression of tumor necrosis factor-a (TNF-a) in cells of the mammal. In a preferred embodiment, the peptide comprises an amino acid sequence is selected from the group consisting of: KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ED NO: 59); KKA VTKAQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 165); VTKAQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 166); AQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 167); KDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 168); KKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 169); KRSRKESYSVYVYKVLKQ (SEQ ID NO: 170); RKESYSVYVYKVLKQ (SEQ ID NO: 171); SYSVYVYKVLKQ (SEQ ID NO: 172); VYVYKVLKQ (SEQ ID NO: 173) and YKVLKQ (SEQ ID NO: 174). In a related preferred embodiment, the dsRNA comprises a ribonucleic acid sequence selected from the group consisting of: GCGUGGAGCUGAGAGAUAA (SEQ ED NO: 109); GCCUGUAGCCCAUGUUGUA (SEQ ID NO: 110); GGUAUGAGCCCAUCUAUCU (SEQ ID NO: 111); CCAGGGACCUCUCUCUAAU (SEQ ID NO: 112); GCCCGACUAUCUCGACUUU (SEQ ID NO: 113); UGACAAGCCUGUAGCCCAU (SEQ ID NO: 114); GGUCUACUUUGGGAUCAUU (SEQ ID NO: 115); CCCAGGGACCUCUCUCUAA (SEQ ID NO: 116); AAUCGGCCCGACUAUCUCGACUU (SEQ ID NO: 117); AAUGGCGUGGAGCUGAGAGAU (SEQ ED NO: 118); AACCUCCUCUCUGCCAUCAAG (SEQ ID NO: 119); AACUGAAAGCAUGAUCCGGGA (SEQ ID NO: 120); AAUCUCGACUUUGCCGAGUCU (SEQ ID NO: 121); AAGGGUGACCGACUCAGCGCU (SEQ ED NO: 122); AAUCAGCCGCAUCGCCGUCUC (SEQ ED NO: 123); AACCCAUGUGCUCCUCACCCA (SEQ ID NO: 124); AAGCUCCAGUGGCUGAACCGC (SEQ ED NO: 125); AAGUCAGAUCAUCUUCUCGAA (SEQ ID NO: 126); AAGGGACCUCUCUCUAAUCAG (SEQ ID NO: 127); CCUCAGCCUCUUCUCCUUCCUGA (SEQ ID NO: 128); AAUCCUCAGCCUCUUCUCCUU (SEQ ID NO: 129); AACCAAUGCCCUCCUGGCCAA (SEQ ID NO: 130); CUGAUUAAGUUGUCUAAACAA (SEQ ID NO: 131); CCGACUCAGCGCUGAGAUCAA (SEQ ID NO: 132); CUUGUGAUUAUUUAUUAUUUA (SEQ ID NO: 133); AAGCCUGUAGCCCAUGUUGUA (SEQ ID NO: 134); UAGGGUCGGAACCCAAGCUUA (SEQ ED NO: 135); CUGAAAGCAUGAUCCGGGA (SEQ DO NO: 136); AGGCGGUGCUUGUUCCUCA (SEQ ID NO: 137); CCACCACGCUCUUCUGCCU (SEQ ID NO: 138); AGGGACCUCUCUCUAAUCA (SEQ ED NO: 139); UGACAAGCCUGUAGCCCAU (SEQ ED NO: 140); GCCUGUAGCCCAUGUUGUA (SEQ ID NO: 141); UAGCCCAUGUUGUAGCAAA (SEQ ED NO: 142); CCAAUGCCCUCCUGGCCAA (SEQ ID NO: 143); CCAAUGGCGUGGAGCUGAG (SEQ ID NO: 144); GGCGUGGAGCUGAGAGAUA (SEQ ID NO: 145); GCGUGGAGCUGAGAGAUAA (SEQ ID NO: 146); GCCUGUACCUCAUCUACUC (SEQ ID NO: 147); CCUCCUCUCUGCCAUCAAG (SEQ ID NO: 148); GGUAUGAGCCCAUCUAUCU (SEQ ED NO: 149); GCUGGAGAAGGGUGACCGA (SEQ ED NO: 150); GAGAAGGGUGACCGACUCA (SEQ ID NO: 151); GCCCGACUAUCUCGACUUU (SEQ ID NO: 152); GCAGGUCUACUUUGGGAUC (SEQ ID NO: 153); GGUCUACUUUGGGAUCAUU (SEQ ID NO: 154); UGGGAUCAUUGCCCUGUGA (SEQ ID NO: 155); GGUCGGAACCCAAGCUUAG (SEQ ED NO: 156); CCAGAAUGCUGCAGGACUU (SEQ ID NO: 157); GAGAAGACCUCACCUAGAA (SEQ ED NO: 158); GAAGACCUCACCUAGAAAU (SEQ ED NO: 159); CCAGAUGUUUCCAGACUUC (SEQ ED NO: 160); CUAUUUAUGUUUGCACUUG (SEQ ID NO: 161); UCUAAACAAUGCUGAUUUG (SEQ ID NO: 162); and GACCAACUGUCACUCAUU (SEQ ED NO: 163). Most preferably, the dsRNA comprises a ribonucleic acid sequence selected from the group consisting of: AAUCGGCCCGACUAUCUCGACUU (SEQ ID NO: 117); AAUGGCGUGGAGCUGAGAGAU (SEQ ID NO: 118); AACCUCCUCUCUGCCAUCAAG (SEQ ED NO: 119); AACUGAAAGCAUGAUCCGGGA (SEQ ED NO: 120); AAUCUCGACUUUGCCGAGUCU (SEQ ED NO: 121); AAGGGUGACCGACUCAGCGCU (SEQ ID NO: 122); AAUCAGCCGCAUCGCCGUCUC (SEQ ID NO: 123); IACCCAUGUGCUCCUCACCCA (SEQ ID NO: 124); AAGCUCCAGUGGCUGAACCGC (SEQ ID NO.- 125); AAGUCAGAUCAUCUUCUCGAA (SEQ ID NO: 126); AAGGGACCUCUCUCUAAUCAG (SEQ ID NO: 127); CCUCAGCCUCUUCUCCUUCCUGA (SEQ ID NO: 128); AAUCCUCAGCCUCUUCUCCUU (SEQ ID NO: 129); AACCAAUGCCCUCCUGGCCAA (SEQ ID NO: 130); CUGAUUAAGUUGUCUAAACAA (SEQ ID NO: 131); CCGACUCAGCGCUGAGAUCAA (SEQ ID NO: 132); CUUGUGAUUAUUUAUUAUUUA (SEQ ID NO: 133); AAGCCUGUAGCCCAUGUUGUA (SEQ ID NO: 134); and UAGGGUCGGAACCCAAGCUUA (SEQ ID NO: 135). BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates peptide-mediated uptake and the effect on cell viability of siRNAs complexed or conjugated to a polynucleotide delivery-enhancing polypeptide of the invention (SEQ ID NO: 35). Cell uptake and cell viability are expressed in percent. Figure 2 further illustrates peptide-mediated uptake of siRNAs complexed or conjugated to a polynucleotide delivery-enhancing polypeptide of the invention (SEQ ID NO: 35). Cell uptake is expressed as mean fluorescent intensity (MFI). Figure 3 shows peptide-mediated uptake of siRNAs in human monocytes with several different polynucleotide delivery-enhancing polypeptides. Figure 4 shows that siRNA/peptide injected mice have a delayed RA progression comparable to that exhibited by Ramicade-treated subjects. RA progression was measured by a paw scoring index. Figure 5 provides results of uptake efficacy and viability studies in mouse tail fibroblast cells for PN73 rationally-designed derivative polynucleotide delivery-enhancing polypeptides of the invention. Figure 6 shows that siNAs conjugated to a polynucleotide delivery-enhancing polypeptide have greater knockdown activity in vitro than siRNAs complexed with a polynucleotide delivery-enhancing polypeptide. DESCRIPTION OF EXEMPLARY EMBODIMENTS OF THE INVENTION The present invention satisfies these needs and fulfills additional objects and advantages by providing novel compositions and methods that employ a short interfering nucleic acid (siNA), or a precursor thereof, in combination with a polynucleotide delivery-enhancing polypeptide. The polynucleotide delivery-enhancing polypeptide is a natural or artificial polypeptide selected for its ability to enhance intracellular delivery or uptake of polynucleotides, including siNAs and their precursors. Within the novel compositions of the invention, the siNA may be admixed or complexed with, or conjugated to, the polynucleotide delivery-enhancing polypeptide to form a composition that enhances intracellular delivery of the siNA as compared to delivery resulting from contacting the target cells with a naked siNA (i.e., siNA without the delivery-enhancing polypeptide present). Enhancer Peptides As used herein "cell" is used in its usual biological sense, and does not refer to an entire multicellular organism, e.g., specifically does not refer to a human. The cell can be present in an organism, e.g., birds, plants and mammals such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats. The cell can be prokaryotic (e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell). The cell can be of somatic or germ line origin, totipotent or pluripotent, dividing or non-dividing. The cell can also be derived from or can comprise a gamete or embryo, a stem cell, or a fully differentiated cell. By "vectors" is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid. By "comprising" is meant including, but not limited to, whatever follows the word "comprising." Thus, use of the term "comprising" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present. By "consisting of is meant including, and limited to, whatever follows the phrase "consisting of." Thus, the phrase "consisting of indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements. The term "biodegradable" as used herein, refers to degradation in a biological system, for example enzymatic degradation or chemical degradation. The term "biologically active molecule" as used herein, refers to compounds or molecules that are capable of fciting or modifying a biological response in a system. Non-limiting examples of biologically active siNA molecules either alone or in combination with other molecules contemplated by the instant invention include therapeutically active molecules such as antibodies, cholesterol, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, 2,5-A chimeras, siNA, dsRNA, allozymes, aptamers, decoys and analogs thereof. Biologically active molecules of the invention also include molecules capable of modulating the pharmacokinetics and/or pharmacodynamics of other biologically active molecules, for example, lipids and polymers such as polyamines, polyamides, polyethylene glycol and other polyethers. The term "phospholipid" as used herein, refers to a hydrophobic molecule comprising at least one phosphorus group. For example, a phospholipid can comprise a phosphorus-containing group and saturated or unsaturated alkyl group, optionally substituted with OH, COOH, oxo, amine, or substituted or unsubstituted aryl groups. The term "ligand" refers to any compound or molecule, such as a drug, peptide, hormone, or neurotransmitter, that is capable of interacting with another compound, such as a receptor, either directly or indirectly. The receptor that interacts with a ligand can be present on the surface of a cell or can alternately be an intracellular receptor. Interaction of the ligand with the receptor can result in a biochemical reaction, or can simply be a physical interaction or association. By the term "non-nucleotide" is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine and therefore lacks a base at the 1 '-position. By "nucleotide" as used herein is as recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1' position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. The nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and other; see, for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No. WO 92/07065; Usman et al, International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra, all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al, 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of base modifications that can be introduced into nucleic acid molecules include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, and others (Burgin et al., 1996, Biochemistry, 35, 14090; Uhlman & Peyman, supra). By "modified bases" in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1' position or their equivalents. By "target site" is meant a sequence within a target RNA that is "targeted" for cleavage mediated by a siNA construct which contains sequences within its antisense region that are complementary to the target sequence. By "detectable level of cleavage" is meant cleavage of target RNA (and formation of cleaved product RNAs) to an extent sufficient to discern cleavage products above the background of RNAs produced by random degradation of the target RNA. Production of cleavage products from 1-5% of the target RNA is sufficient to detect above the background for most methods of detection. By "biological system" is meant, material, in a purified or unpurified form, from biological sources, including but not limited to human, animal, plant, insect, bacterial, viral or other sources, wherein the system comprises the components required for RNAi activity. The term "biological system" includes, for example, a cell, tissue, or organism, or extract thereof. The term biological system also includes reconstituted RNAi systems that can be used in an in vitro setting. The term "biodegradable linker" as used herein, refers to a nucleic acid or non-nucleic acid linker molecule that is designed as a biodegradable linker to connect one molecule to another molecule, for example, a biologically active molecule to a siNA molecule of the invention or the sense and antisense strands of a siNA molecule of the invention. The biodegradable linker is designed such that its stability can be modulated for a particular purpose, such delivery to a particular tissue or cell type. The stability of a nucleic acid-based biodegradable linker molecule can lie modulated by using various chemistries, for example combinations of ribonucleotides, deoxyribonucleotides, and chemically-modified nucleotides, such as 2'-O-methyl, 2'-fluoro, 2'-amino, 2'-O-amino, 2'-C-allyl, 2'-O-allyl, and other 2'-modified or base modified nucleotides. The biodegradable nucleic acid linker molecule can be a dimer, trimer, tetramer or longer nucleic acid molecule, for example, an oligonucleotide of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, or can comprise a single nucleotide with a phosphorus-based linkage, for example, a phosphoramidate or phosphodiester linkage. The biodegradable nucleic acid linker molecule can also comprise nucleic acid backbone, nucleic acid sugar, or nucleic acid base modifications. In certain embodiments of the invention, the polynucleotide delivery-enhancing polypeptide is a histone protein, or a polypeptide or peptide fragment, derivative, analog, or conjugate thereof. Within these embodiments, the siNA is admixed, complexed or conjugated with one or more full length histone proteins or polypeptides corresponding at least in part to a partial sequence of a histone protein, for example of one or more of the following histones: histone HI, histone H2A, histone H2B, histone H3 or histone H4, or one or more polypeptide fragments or derivatives thereof comprising at least a partial sequence of a histone protein, typically at least 5-10 or 10-20 contiguous residues of a native histone protein. In more detailed embodiments, the siRNA/histone mixture, complex or conjugate is substantially free of amphipathic compounds. In other detailed embodiments, the siNA that is admixed, complexed, or conjugated with the histone protein or polypeptide will comprise a double-stranded double-stranded RNA, for example a double-stranded RNA that has 30 or fewer nucleotides, and is a short interfering RNA (siRNA). In exemplary embodiments, the histone polynucleotide delivery-enhancing polypeptide comprises a fragment of histone H2B, as exemplified by the polynucleotide delivery-enhancing polypeptide designated PN73 described herein below. In yet additional detailed embodiments, the polynucleotide delivery-enhancing polypeptide may be pegylated to improve stability and/or efficacy, particularly in the context of in vivo administration. Within additional embodiments of the invention, the polynucleotide delivery-enhancing polypeptide is selected or rationally designed to comprise an amphipathic amino acid sequence. For example, useful polynucleotide deliveryenhancing polypeptides may be selected which comprise a plurality of non-polar or hydrophobic amino acid residues that form a hydrophobic sequence domain or motif, linked to a plurality of charged amino acid residues that form a charged sequence domain or motif, yielding an amphipathic peptide. In other embodiments, the polynucleotide delivery-enhancing polypeptide is selected to comprise a protein transduction domain or motif, and a fusogenic peptide domain or motif. A protein transduction domain is a peptide sequence that is able to insert into and preferably transit through the membrane of cells. A fusogenic peptide is a peptide that destabilizes a lipid membrane, for example a plasma membrane or membrane surrounding an endosome, which may be enhanced at low pH. Exemplary fusogenic domains or motifs are found in a broad diversity of viral fusion proteins and in other proteins, for example fibroblast growth factor 4 (FGF4). To rationally design polynucleotide delivery-enhancing polypeptides of the invention, a protein transduction domain is employed as a motif that will facilitate entry of the nucleic acid into a cell through the plasma membrane. In certain embodiments, the transported nucleic acid will be encapsulated in an endosome. The interior of endosomes has a low pH resulting in the fusogenic peptide motif destabilizing the membrane of the endosome. The destabilization and breakdown of the endosome membrane allows for the release of the siNA into the cytoplasm where the siNA can associate with a RISC complex and be directed to its target mRNA. Exemplary polynucleotide delivery-enhancing polypeptides within the invention may be selected from the following peptides: WWETWKPFQCRICMRNFSTRQARRNHRRRHR (SEQ ID NO: 27); GKINLKALAALAKKIL (SEQ ID NO: 28), RVIRVWFQNKRCKDKK (SEQ ID NO: 29), GRKKRRQRRRPPQGRKKRRQRRRPPQGRKKRRQRRRPPQ (SEQ ID NO: 30), GEQIAQLIAGYIDIILKKKKSK (SEQ ID NO: 31), Poly Lys-Trp, 4:1, MW 20,000-50,000; and Poly Orn-Trp, 4:1, MW 20,000-50,000. Additional polynucleotide delivery-enhancing polypeptides that are useful within the compositions and methods herein comprise all or part of the mellitin protein sequence. Still other exemplary polynucleotide delivery-enhancing polypeptides are identified in the examples below. Any one or combination of these peptides may be selected or combined to yield effective polynucleotide deliveryenhancing polypeptide reagents to induce or facilitate intracellular delivery of siNAs within the methods and compositions of the invention. In more detailed aspects of the invention, the mixture, complex or conjugate comprising a siRNA and a 'lynucleotide delivery-enhancing polypeptide can be optionally combined with (e.g., admixed or complexed with) a cationic lipid, such as LIPOFECTIN* In this context it is unexpectedly disclosed herein that polynucleotide deliveryenhancing polypeptides complexed or conjugated to a siRNA alone will effectuate delivery of the siNA sufficient to mediate gene silencing by RNAi. However, it is further unexpectedly disclosed herein that a siRNA/polynucleotide delivery-enhancing polypeptide complex or conjugate will exhibit even greater activity for mediating siNA delivery and gene silencing when admixed or complexed with a cationic lipid, such as lipofectin. To produce these compositions comprised of a polynucleotide delivery-enhancing polypeptide, siRNA and a cationic lipid, the siRNA and peptide may be mixed together first in a suitable medium such as a cell culture medium, after which the cationic lipid is added to the mixture to form a siRNA/delivery peptide/cationic lipid composition. Optionally, the peptide and cationic lipid can be mixed together first in a suitable medium such as a cell culture medium, where after the siRNA can be added to form the siRNA/delivery peptide/cationic lipid composition. Examples of useful cationic lipids within these aspects of the invention include N-[l-(2,3-dioleoyloxy)propyl]- N,N,N-trimethylammonium chloride, 1,2-bis(oleoyloxy)-3-3-(trimethylammonium)propane, 1,2-dimyristyloxypropyl- 3-dimethylhydroxyethylammonium bromide, and dimethyldioctadecylammonium bromide, 2,3-dioleyloxy-N- [2(sperminecarboxamido)ethyl]-N,N-dimethyl-l -propanaminiu m trifluoracetate, 1,3-dioleoyloxy-2-(6- carboxyspermyl)-propylamid, 5-carboxyspermylglycine dioctadecylamide, tetramethyltetrapalmitoyl spermine, tetramethyltetraoleyl spermine, tetramethyltetralauryl spermine, tetramethyltetramyristyl spermine and tetramethyldioleyl spermine. DOTMA (N-[l-(2,3-dioleoyloxy)propyl]-N,N,N-trimethyl ammonium chloride), DOTAP (l,2-bis(oleoyloxy)-3,3-(trimethylammonium)propane), DMRIE (l,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide) or DDAB (dimethyl dioctadecyl ammonium bromide). Polyvalent cationic lipids include lipospermines, specifically DOSPA (2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-l -propanamini um trifluoro-acetate) and DOSPER (l,3-dioleoyloxy-2-(6carboxy spermyl)-propyl-amid, and the di- and tetra-alkyltetra- methyl spermines, including but not limited to TMTPS (tetramethyltetrapalmitoyl spermine), TMTOS (tetramethyltetraoleyl spermine), TMTLS (tetramethlytetralauryl spermine), TMTMS (tetramethyltetramyristyl spermine) and TMDOS (tetramethyldioleyl spermine) DOGS (dioctadecyl-amidoglycylspermine (TRANSFECTAM1. Other useful cationic lipids are described, for example, in U.S. Patent No. 6,733,777; U.S. Patent No. 6,376,248; U.S. Patent No. 5,736,392; U.S. Patent No. 5,686,958; U.S. Patent No. 5,334,761 and U.S. Patent No. 5,459,127. Cationic lipids are optionally combined with non-cationic lipids, particularly neutral lipids, for example lipids such as DOPE (dioleoylphosphatidylethanolamine), DPhPE (diphytanoylphosphatidylethanolamine) or cholesterol. A cationic lipid composition composed of a 3:1 (w/w) mixture of DOSPA and DOPE or a 1:1 (w/w) mixture of DOTMA and DOPE (LIPOFECTIN*, Invitrogen) are generally useful in transfecting compositions of this invention. Preferred transfection compositions are those which induce substantial transfection of a higher eukaryotic cell line. Double stranded siRNA molecules By "asymmetric hairpin" as used herein is meant a linear siNA molecule comprising an antisense region, a loop portion that can comprise nucleotides or non-nucleotides, and a sense region that comprises fewer nucleotides than the antisense region to the extent that the sense region has enough complementary nucleotides to base pair with the antisense region and form a duplex with loop. For example, an asymmetric hairpin siNA molecule of the invention can comprise an antisense region having length sufficient to mediate RNAi in a T-cell (e.g. about 19 to about 22 (e.g., about 19, 20, 21, or 22) nucleotides) and a loop region comprising about 4 to about 8 (e.g., about 4, 5, 6, 7, or 8) nucleotides, and a sense region having about 3 to about 18 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) nucleotides that are complementary to the antisense region. The asymmetric hairpin siNA molecule can also comprise a 5'-terminal phosphate group that can be chemically modified. The loop portion of the asymmetric hairpin siNA molecule can comprise nucleotides, non-nucleotides, linker molecules, or conjugate molecules as described herein. By "asymmetric duplex" as used herein is meant a siNA molecule having two separate strands comprising a sense region and an antisense region, wherein the sense region comprises fewer nucleotides than the antisense region to the extent that the sense region has enough complementary nucleotides to base pair with the antisense region and form a duplex. For example, an asymmetric duplex siNA molecule of the invention can comprise an antisense region having length sufficient to mediate RNAi in a T-cell (e.g. about 19 to about 22 (e.g. about 19, 20, 21, or 22) nucleotides) and a sense region having about 3 to about 18 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) nucleotides that are complementary to the antisense region. By "modulate gene expression" is meant that the expression of a target gene is upregulated or downregulated, which can include upregulation or downregulation of mRNA levels present in a cell, or of mRNA translation, or of synthesis of protein or protein subunits, encoded by the target gene. Modulation of gene expression can be determined also be the presence, quantity, or activity of one or more proteins or protein subunits encoded by the target gene that is up regulated or down regulated, such that expression, level, or activity of the subject protein or subunit is greater than or less than that which is observed in the absence of the modulator (e.g., a siRNA). For example, the term "modulate" can mean "inhibit," but the use of the word "modulate" is not limited to this definition. By "inhibit", "down-regulate", or "reduce" expression, it is meant that the expression of the gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits, or level or activity of one or more proteins or protein subunits encoded by a target gene, is reduced below that observed in the absence of the nucleic acid molecules (e.g., siNA) of the invention. In one embodiment, inhibition, down-regulation or reduction with an siNA molecule is below that level observed in the presence of an inactive or attenuated molecule. In another embodiment, inhibition, down-regulation, or reduction with siNA molecules is below that level observed in the presence of, for example, an siNA molecule with scrambled sequence or with mismatches. In another embodiment, inhibition, down-regulation, or reduction of gene expression with a nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence. Gene "silencing" refers to partial or complete loss-of-function through targeted inhibition of gene expression in a cell and may also be referred to as "knock down". Depending on the circumstances and the biological problem to be addressed, it may be preferable to partially reduce gene expression. Alternatively, it might be desirable to reduce gene expression as much as possible. The extent of silencing may be determined by methods known in the art, some of which are summarized in International Publication No. WO 99/32619. Depending on the assay, quantification of gene expression permits detection of various amounts of inhibition that may be desired in certain embodiments of the invention, including prophylactic and therapeutic methods, which will be capable of knocking down target gene expression, in terms of mRNA levels or protein levels or activity, for example, by equal to or greater than 10%, 30%, 50%, 75% 90%, 95% or 99% of baseline (i.e., normal) or other control levels, including elevated expression levels as may be associated with particular disease states or other conditions targeted for therapy. The phrase "inhibiting expression of a target gene" refers to the ability of a siNA of the invention to initiate gene silencing of the target gene. To examine the extent of gene silencing, samples or assays of the organism of interest or cells in culture expressing a particular construct are compared to control samples lacking expression of the construct. Control samples (lacking construct expression) are assigned a relative value of 100%. Inhibition of expression of a target gene is achieved when the test value relative to the control is about 90%, often 50%, and in certain embodiments 25-0%. Suitable assays include, e.g., examination of protein or mRNA levels using techniques known to those of skill in the art such as dot blots, northern blots, in situ hybridization, ELISA, immunoprecipitation, enzyme function, as well as phenotypic assays known to those of skill in die art. By "subject" is meant an organism, tissue, or cell, which may include an organism as the subject or as a donor or recipient of explanted cells or the cells that are themselves subjects for siNA delivery. "Subject" therefore may refers to an organism, organ, tissue, or cell, including in vitro or ex vivo organ, tissue or cellular subjects, to which the nucleic acid molecules of the invention can be administered and enhanced by polynucleotide delivery-enhancing polypeptides described herein. Exemplary subjects include mammalian individuals or cells, for example human patients or cells. By "RNA" is meant a molecule comprising at least one ribonucleotide residue. By "ribonucleotide" is meant a nucleotide with a hydroxyl group at the 2' position of a .beta.-D-ribo-furanose moiety. The terms include double-stranded RNA, single-stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as altered RNA that differs from naturally occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations can include addition of non-nucleotide material, such as to the end(s) of the siNA or internally, for example at one or more nucleotides of the RNA. Nucleotides in the RNA molecules of the instant invention can also comprise non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. These altered RNAs can be referred to as analogs or analogs of naturally-occurring RNA. By "highly conserved sequence region" is meant, a nucleotide sequence of one or more regions in a target gene does not vary significantly from one generation to the other or from one biological system to the other. By "sense region" is meant a nucleotide sequence of a siNA molecule having complementarity to an antisense region of the siNA molecule. In addition, the sense region of a siNA molecule can comprise a nucleic acid sequence having homology with a target nucleic acid sequence. By "antisense region" is meant a nucleotide sequence of a siNA molecule having complementarity to a target aeicleic acid sequence. In addition, the antisense region of a siNA molecule can optionally comprise a nucleic acid sequence having complementarity to a sense region of the siNA molecule. By "target nucleic acid" is meant any nucleic acid sequence whose expression or activity is to be modulated. The target nucleic acid can be DNA or RNA. By "complementarity" is meant that a nucleic acid can form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., RNAi activity. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al., 1987, CSH Symp. Quant. Biol. LII pp. 123- 133; Frier et al., 1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc. 109:3783- 3785). A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule that can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, or 10 nucleotides out of a total of 10 nucleotides in the first oligonucleotide being based paired to a second nucleic acid sequence having 10 nucleotides represents 50%, 60%, 70%, 80%, 90%, and 100% complementary respectively). "Perfectly complementary" means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. The term "universal base" as used herein refers to nucleotide base analogs that form base pairs with each of the natural DNA/RNA bases with little discrimination between them. Non-limiting examples of universal bases include Cphenyl, C-naphthyl and other aromatic derivatives, inosine, azole carboxamides, and nitroazole derivatives such as 3- nitropyrrole, 4-nitroindole, 5-nitroindole, and 6-nitroindole as known in the art (see for example Loakes, 2001, Nucleic Acids Research, 29, 2437-2447). The term "acyclic nucleotide" as used herein refers to any nucleotide having an acyclic ribose sugar, for example where any of the ribose carbons (Cl, C2, C3, C4, or C5), are independently or in combination absent from the nucleotide. By "abasic" is meant sugar moieties lacking a base or having other chemical groups in place of a base at the 1' position, see for example Adamic et al., U.S. Pat. No. 5,998,203. By "unmodified nucleoside" is meant one of the bases adenine, cytosine, guanine, thymine, or uracil joined to the 1'carbon of beta.-D-ribo-furanose. By "modified nucleoside" is meant any nucleotide base which contains a modification in the chemical structure of an unmodified nucleotide base, sugar and/or phosphate. Non-limiting examples of modified nucleotides are shown by Formulae I-VII and/or other modifications described herein. By "cap structure" is meant chemical modifications, which have been incorporated at either terminus of the oligonucleotide (see, for example, Adamic et al., U.S. Pat. No. 5,998,203, incorporated by reference herein). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and may help in delivery and/or localization within a cell. The cap may be present at the 5'-terminus (5'-cap) or at the 3'-terminal (3'-cap) or may be present on both termini. In non-limiting examples, the 5'-cap includes, but is not limited to, glyceryl, inverted deoxy abasic residue (moiety); 4',5'-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide, 4'-thio nucleotide; carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage; threo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide, 3'-3'-inverted nucleotide moiety; 3'-3'-inverted abasic moiety; 3'- 2'-inverted nucleotide moiety; 3'-2'-inverted abasic moiety; 1,4-butanediol phosphate; 3'-phosphoramidate; hexylphosphate; aminohexyl phosphate; 3'-phosphate; 3'-phosphorothioate; phosphorodithioate; or bridging or nonbridging methylphosphonate moiety. Non-limiting examples of the 3'-cap include, but are not limited to, glyceryl, inverted deoxy abasic residue (moiety), 4',5'-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4'-thio nucleotide, carbocyclic nucleotide; 5'-amino-alkyl phosphate; l,3-diamino-2-propyl phosphate; 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5'-5'-inverted nucleotide moiety; 5'-5'- inverted abasic moiety; 5'-phosphoramidate; 5'-phosphorothioate; 1,4-butanediol phosphate; 5'-amino; bridging and/or non-bridging 5'-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5'-mercapto moieties (for more details see Beaucage and Lyer, 1993, Tetrahedron 49, 1925; incorporated by reference herein). In connection with 2'-modified nucleotides as described for the present invention, by "amino" is meant 2'-NH2 or 2'-O--NH2, which can be modified or unmodified. Such modified groups are described, for example, in Eckstein et al., U.S. Pat. No. 5,672,695 and Matulic-Adamic et al., U.S. Patent. No. 6,248,878. The siNA molecules can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues. The nucleic acid or nucleic acid complexes can be locally administered to through injection, infusion pump or stent, with or without their incorporation in biopolymers. In another embodiment, polyethylene glycol (PEG) can be covalently attached to siNA compounds of the present invention, to the polynucleotide deliveryenhancing polypeptide, or both. The attached PEG can be any molecular weight, preferably from about 2,000 to about 50,000 daltons (Da). The sense region can be connected to the antisense region via a linker molecule, such as a polynucleotide linker or a non-nucleotide linker. "Inverted repeat" refers to a nucleic acid sequence comprising a sense and an antisense element positioned so that they are able to form a double stranded siRNA when the repeat is transcribed. The inverted repeat may optionally include a linker or a heterologous sequence such as a self-cleaving ribozyme between the two elements of the repeat. The elements of the inverted repeat have a length sufficient to form a double stranded RNA. Typically, each element of the inverted repeat is about 15 to about 100 nucleotides in length, preferably about 20-30 base nucleotides, preferably about 20-25 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. "Nucleic acid" refers to deoxyribonucleotides or ribonucleotides and polymers thereof in single- or doublestranded form. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs). "Large double-stranded RNA" refers to any double-stranded RNA having a size greater than about 40 base pairs (bp) for example, larger than 100 bp or more particularly larger than 300 bp. The sequence of a large dsRNA may represent a segment of a mRNA or the entire mRNA. The maximum size of the large dsRNA is not limited herein. The double-stranded RNA may include modified bases where the modification may be to the phosphate sugar backbone or to the nucleoside. Such modifications may include a nitrogen or sulfur heteroatom or any other modification known in the art. The double-stranded structure may be formed by self-complementary RNA strand such as occurs for a hairpin or a micro RNA or by annealing of two distinct complementary RNA strands. "Overlapping" refers to when two RNA fragments have sequences which overlap by a plurality of nucleotides on one strand, for example, where the plurality of nucleotides (nt) numbers as few as 2-5 nucleotides or by 5-10 nucleotides or more. "One or more dsRNAs" refers to dsRNAs that differ from each other on the basis of sequence. "Target gene or mRNA" refers to any gene or mRNA of interest. Indeed any of the genes previously identified by genetics or by sequencing may represent a target. Target genes or mRNA may include developmental genes and regulatory genes as well as metabolic or structural genes or genes encoding enzymes. The target gene may be expressed in those cells in which a phenotype is being investigated or in an organism in a manner that directly or indirectly impacts a phenotypic characteristic. The target gene may be endogenous or exogenous. Such cells include any cell in the body of an adult or embryonic animal or plant including gamete or any isolated cell such as occurs in an immortal cell line or primary cell culture. hi exemplary embodiments, the instant invention features compositions comprising a small nucleic acid molecule, such as short interfering nucleic acid (siNA), a short interfering RNA (siRNA), a double-stranded RNA micro-RNA (mRNA), or a short hairpin RNA (shRNA), admixed or complexed with, or conjugated to, a j%rynucleotide delivery-enhancing polypeptide. As used herein, the term "short interfering nucleic acid", "siNA", "short interfering RNA", "siRNA", "short interfering nucleic acid molecule", "short interfering oligonucleotide molecule", or "chemically-modified short interfering nucleic acid molecule", refers to any nucleic acid molecule capable of inhibiting or down regulating gene expression or viral replication, for example by mediating RNA interference "RNAi" or gene silencing in a sequencespecific manner. Within exemplary embodiments, the siNA is a double-stranded polynucleotide molecule comprising self-complementary sense and antisense regions, wherein the antisense region comprises a nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule for down regulating expression, or a portion thereof, and the sense region comprises a nucleotide sequence corresponding to (i.e., which is substantially identical in sequence to) the target nucleic acid sequence or portion thereof. "siNA" means a small interfering nucleic acid, for example a siRNA, that is a short-length double-stranded nucleic acid (or optionally a longer precursor thereof), and which is not unacceptably toxic in target cells. The length of useful siNAs within the invention will in certain embodiments be optimized at a length of approximately 21 to 23 bp long. However, there is no particular limitation in the length of useful siNAs, including siRNAs. For example, siNAs can initially be presented to cells in a precursor form that is substantially different than a final or processed form of the siNA that will exist and exert gene silencing activity upon delivery, or after delivery, to the target cell. Precursor forms of siNAs may, for example, include precursor sequence elements that are processed, degraded, altered, or cleaved at or following the time of delivery to yield a siNA that is active within the cell to mediate gene silencing. Thus, in certain embodiments, useful siNAs within the invention will have a precursor length, for example, of approximately 100-200 base pairs, 50-100 base pairs, or less than about 50 base pairs, which will yield an active, processed siNA within the target cell. In other embodiments, a useful siNA or siNA precursor will be approximately 10 to 49 bp, 15 to 35 bp, or about 21 to 30 bp in length. In certain embodiments of the invention, as noted above, polynucleotide delivery-enhancing polypeptides are used to facilitate delivery of larger nucleic acid molecules than conventional siNAs, including large nucleic acid precursors of siNAs. For example, the methods and compositions herein may be employed for enhancing delivery of larger nucleic acids that represent "precursors" to desired siNAs, wherein the precursor amino acids may be cleaved or otherwise processed before, during or after delivery to a target cell to form an active siNA for modulating gene expression within the target cell. For example, a siNA precursor polynucleotide may be selected as a circular, singlestranded polynucleotide, having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region comprises a nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule or a portion thereof, and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active siNA molecule capable of mediating RNAi. In mammalian cells, dsRNAs longer than 30 base pairs can activate the dsRNA-dependent kinase PKR and 2'- 5'-oligoadenylate synthetase, normally induced by interferon. The activated PKR inhibits general translation by phosphorylation of the translation factor eukaryotic initiation factor 2x (eIF2a), while 2'-5'-oligoadenylate synthetase causes nonspecific mRNA degradation via activation of RNase L. By virtue of their small size (referring particularly to non-precursor forms), usually less than 30 base pairs, and most commonly between about 17-19, 19-21, or 21-23 base pairs, the siNAs of the present invention avoid activation of the interferon response. In contrast to the nonspecific effect of long dsRNA, siRNA can mediate selective gene silencing in the mammalian system. Hairpin RNAs, with a short loop and 19 to 27 base pairs in the stem, also selectively silence expression of genes that are homologous to the sequence in the double-stranded stem. Mammalian cells can convert short hairpin RNA into siRNA to mediate selective gene silencing. RISC mediates cleavage of single stranded RNA having sequence complementary to the antisense strand of the siRNA duplex. Cleavage of the target RNA takes place in the middle of the region complementary to the antisense strand of the siRNA duplex. Studies have shown that 21 nucleotide siRNA duplexes are most active when containing two nucleotide 3'-overhangs. Furthermore, complete substitution of one or both siRNA strands with 2'-deoxy (2'-H) or 2'-O-methyl nucleotides abolishes RNAi activity, whereas substitution of the 3'-terminal siRNA overhang nucleotides with deoxy nucleotides (2'-H) has been reported to be tolerated. Studies have shown that replacing the 3'-overhanging segments of a 21-mer siRNA duplex having 2 nucleotide 3' overhangs with deoxyribonucleotides does not have an adverse effect on RNAi activity. Replacing up to 4 nucleotides on each end of the siRNA with deoxyribonucleotides has been reported to be well tolerated whereas (Iffhplete substitution with deoxyribonucleotides results in no RNAi activity. Alternatively, the siNAs can be delivered as single or multiple transcription products expressed by a polynucleotide vector encoding the single or multiple siNAs and directing their expression within target cells. In these embodiments the double-stranded portion of a final transcription product of the siRNAs to be expressed within the target cell can be, for example, 15 to 49 bp, 15 to 35 bp, or about 21 to 30 bp long. Within exemplary embodiments, double-stranded portions of siNAs, in which two strands pair up, are not limited to completely paired nucleotide segments, and may contain nonpairing portions due to mismatch (the corresponding nucleotides are not complementary), bulge (lacking in the corresponding complementary nucleotide on one strand), overhang, and the like. Nonpairing portions can be contained to the extent that they do not interfere with siNA formation. In more detailed embodiments, a "bulge" may comprise 1 to 2 nonpairing nucleotides, and the double-stranded region of siNAs in which two strands pair up may contain from about 1 to 7, or about 1 to 5 bulges. In addition, "mismatch" portions contained in the double-stranded region of siNAs may be present in numbers from about 1 to 7, or about 1 to 5. Most often in the case of mismatches, one of the nucleotides is guanine, and the other is uracil. Such mismatching may be attributable, for example, to a mutation from C to T, G to A, or mixtures thereof, in a corresponding DNA coding for sense RNA, but other cause are also contemplated. Furthermore, in the present invention the double-stranded region of siNAs in which two strands pair up may contain both bulge and mismatched portions in the approximate numerical ranges specified. The terminal structure of siNAs of the invention may be either blunt or cohesive (overhanging) as long as the siNA retains its activity to silence expression of target genes. The cohesive (overhanging) end structure is not limited only to the 3' overhang as reported by others. On the contrary, the 5' overhanging structure may be included as long as it is capable of inducing a gene silencing effect such as by RNAi. In addition, the number of overhanging nucleotides is not limited to reported limits of 2 or 3 nucleotides, but can be any number as long as the overhang does not impair gene silencing activity of the siNA. For example, overhangs may comprise from about 1 to 8 nucleotides, more often from about 2 to 4 nucleotides. The total length of siNAs having cohesive end structure is expressed as the sum of the length of the paired double-stranded portion and that of a pair comprising overhanging single-strands at both ends. For example, in the exemplary case of a 19 bp double-stranded RNA with 4 nucleotide overhangs at both ends, the total length is expressed as 23 bp. Furthermore, since the overhanging sequence may have low specificity to a target gene, it is not necessarily complementary (antisense) or identical (sense) to the target gene sequence. Furthermore, as long as the siNA is able to maintain its gene silencing effect on the target gene, it may contain low molecular weight structure (for example a natural RNA molecule such as tRNA, rRNA or viral RNA, or an artificial RNA molecule), for example, in the overhanging portion at one end. In addition, the terminal structure of the siNAs may have a stem-loop structure in which ends of one side of the double-stranded nucleic acid are connected by a linker nucleic acid, e.g., a linker RNA. The length of the doublestranded region (stem-loop portion) can be, for example, 15 to 49 bp, often 15 to 35 bp, and more commonly about 21 to 30 bp long. Alternatively, the length of the double-stranded region that is a final transcription product of siNAs to be expressed in a target cell may be, for example, approximately 15 to 49 bp, 15 to 35 bp, or about 21 to 30 bp long. When linker segments are employed, there is no particular limitation in the length of the linker as long as it does not hinder pairing of the stem portion. For example, for stable pairing of the stem portion and suppression of recombination between DNAs coding for this portion, the linker portion may have a clover-leaf tRNA structure. Even if the linker has a length that would hinder pairing of the stem portion, it is possible, for example, to construct the linker portion to include introns so that the introns are excised during processing of a precursor RNA into mature RNA, thereby allowing pairing of the stem portion. In the case of a stem-loop siRNA, either end (head or tail) of RNA with no loop structure may have a low molecular weight RNA. As described above, these low molecular weight RNAs may include a natural RNA molecule, such as tRNA, rRNA or viral RNA, or an artificial RNA molecule. The siNA can also comprise a single stranded polynucleotide having nucleotide sequence complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof (for example, where such siNA molecule does not require the presence within the siNA molecule of nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof), wherein the single stranded polynucleotide can further comprise a terminal phosphate group, such as a 5'-phosphate (see for example Martinez et al.,Cell., 110: 563-574 (2002) and Schwarz et al., Molecular Cell, 10: 537-568(2002), or 5',3'-diphosphate. As used herein, the term siNA molecule is not limited to molecules containing only naturally-occurring RNA or DNA, but also encompasses chemically-modified nucleotides and non-nucleotides. In certain embodiments, the short interfering nucleic acid molecules of the invention lack 2'-hydroxy (2'-OH) containing nucleotides. In certain - 12. rembodiments short interfering nucleic acids do not require the presence of nucleotides having a 2'-hydroxy group for mediating RNAi and as such, short interfering nucleic acid molecules of the invention optionally do not include any ribonucleotides (e.g., nucleotides having a 2'-OH group). Such siNA molecules that do not require the presence of ribonucleotides within the siNA molecule to support RNAi can however have an attached linker or linkers or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2'-OH groups. Optionally, siNA molecules can comprise ribonucleotides at about 5, 10, 20, 30, 40, or 50% of the nucleotide positions. As used herein, the term siNA is meant to be equivalent to other terms used to describe nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (mRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically-modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA), and others. In other embodiments, siNA molecules for use within the invention may comprise separate sense and antisense sequences or regions, wherein the sense and antisense regions are covalently linked by nucleotide or non-nucleotide linker molecules, or are alternately non-covalently linked by ionic interactions, hydrogen bonding, van der waals interactions, hydrophobic interactions, and/or stacking interactions. "Antisense RNA" is an RNA strand having a sequence complementary to a target gene mRNA, and thought to induce RNAi by binding to the target gene mRNA. "Sense RNA" has a sequence complementary to the antisense RNA, and annealed to its complementary antisense RNA to form siRNA. These antisense and sense RNAs have been conventionally synthesized with an RNA synthesizer. As used herein, the term "RNAi construct" is a generic term used throughout the specification to include small interfering RNAs (siRNAs), hairpin RNAs, and other RNA species which can be cleaved in vivo to form siRNAs. RNAi constructs herein also include expression vectors (also referred to as RNAi expression vectors) capable of giving rise to transcripts which form dsRNAs or hairpin RNAs in cells, and/or transcripts which can produce siRNAs in vivo. Optionally, the siRNA include single strands or double strands of siRNA. An siHybrid molecule is a double-stranded nucleic acid that has a similar function to siRNA. Instead of a double-stranded RNA molecule, an siHybrid is comprised of an RNA strand and a DNA strand. Preferably, the RNA strand is the antisense strand as that is the strand that binds to the target mRNA. The siHybrid created by the hybridization of the DNA and RNA strands have a hybridized complementary portion and preferably at least one 3'overhanging end. siNAs for use within the invention can be assembled from two separate oligonucleotides, where one strand is the sense strand and the other is the antisense strand, wherein the antisense and sense strands are self-complementary (i.e. each strand comprises nucleotide sequence that is complementary to nucleotide sequence in the other strand; such as where the antisense strand and sense strand form a duplex or double stranded structure, for example wherein the double stranded region is about 19 base pairs). The antisense strand may comprise a nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule or a portion thereof, and the sense strand may comprise a nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. Alternatively, the siNA can be assembled from a single oligonucleotide, where the self-complementary sense and antisense regions of the siNA are linked by means of a nucleic acid-based or non-nucleic acid-based linker(s). Within additional embodiments, siNAs for intracellular delivery according to the methods and compositions of the invention can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises a nucleotide sequence that is complementary to a nucleotide sequence in a separate target nucleic acid molecule or a portion thereof, and the sense region comprises a nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. Non-limiting examples of chemical modifications that can be made in an siNA include without limitation phosphorothioate internucleotide linkages, 2'-deoxyribonucleotides, 2'-O-methyl ribonucleotides, 2'-deoxy-2'-fluoro ribonucleotides, "universal base" nucleotides, "acyclic" nucleotides, 5-C-methyl nucleotides, and terminal glyceryl and/or inverted deoxy abasic residue incorporation. These chemical modifications, when used in various siNA constructs, are shown to preserve RNAi activity in cells while at the same time, dramatically increasing the serum stability of these compounds. In a non-limiting example, the introduction of chemically-modified nucleotides into nucleic acid molecules provides a powerful tool in overcoming potential limitations of in vivo stability and bioavailability inherent to native RNA molecules that are delivered exogenously. For example, the use of chemically-modified nucleic acid molecules can enable a lower dose of a particular nucleic acid molecule for a given therapeutic effect since chemically-modified nucleic acid molecules tend to have a longer half-life in serum. Furthermore, certain chemical modifications can improve the bioavailability of nucleic acid molecules by targeting particular cells or tissues and/or improving cellular uptake of the nucleic acid molecule. Therefore, even if the activity of a chemically-modified nucleic acid molecule is reduced as compared to a native nucleic acid molecule, for example, when compared to an all-RNA nucleic acid molecule, the overall activity of the modified nucleic acid molecule can be greater than that of the native molecule due to improved stability and/or delivery of the molecule. Unlike native unmodified siNA, chemically-modified siNA can also minimize the possibility of activating interferon activity in humans. The siNA molecules described herein, the antisense region of a siNA molecule of the invention can comprise a phosphorothioate internucleotide linkage at the 3'-end of said antisense region. In any of the embodiments of siNA molecules described herein, the antisense region can comprise about one to about five phosphorothioate internucleotide linkages at the 5'-end of said antisense region. In any of the embodiments of siNA molecules described herein, the 3'-terminal nucleotide overhangs of a siNA molecule of the invention can comprise ribonucleotides or deoxyribonucleotides that are chemically-modified at a nucleic acid sugar, base, or backbone. In any of the embodiments of siNA molecules described herein, the 3'-terminal nucleotide overhangs can comprise one or more universal base ribonucleotides. In any of the embodiments of siNA molecules described herein, the 3'-terminal nucleotide overhangs can comprise one or more acyclic nucleotides. For example, in a non-limiting example, the invention features a chemically-modified short interfering nucleic acid (siNA) having about 1, 2, 3, 4, 5, 6, 7, 8 or more phosphorothioate internucleotide linkages in one siNA strand. In yet another embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) individually having about 1, 2, 3, 4, 5, 6, 7, 8 or more phosphorothioate internucleotide linkages in both siNA strands. The phosphorothioate internucleotide linkages can be present in one or both oligonucleotide strands of the siNA duplex, for example in the sense strand, the antisense strand, or both strands. The siNA molecules of the invention can comprise one or more phosphorothioate internucleotide linkages at the 3'-end, the 5'-end, or both of the 3'- and S'-ends of the sense strand, the antisense strand, or both strands. For example, an exemplary siNA molecule of the invention can comprise about 1 to about 5 or more (e.g., about 1, 2, 3, 4, 5, or more) consecutive phosphorothioate internucleotide linkages at the 5'-end of the sense strand, the antisense strand, or both strands. In another non-limiting example, an exemplary siNA molecule of the invention can comprise one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) pyrimidine phosphorothioate internucleotide linkages in the sense strand, the antisense strand, or both strands, hi yet another non-limiting example, an exemplary siNA molecule of the invention can comprise one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) purine phosphorothioate internucleotide linkages in the sense strand, the antisense strand, or both strands. An siNA molecule may be comprised of a circular nucleic acid molecule, wherein the siNA is about 38 to about 70 (e.g., about 38, 40, 45, 50, 55, 60, 65, or 70) nucleotides in length having about 18 to about 23 (e.g., about 18, 19, 20, 21, 22, or 23) base pairs wherein the circular oligonucleotide forms a dumbbell shaped structure having about 19 base pairs and 2 loops. A circular siNA molecule contains two loop motifs, wherein one or both loop portions of the siNA molecule is biodegradable. For example, a circular siNA molecule of the invention is designed such that degradation of the loop portions of the siNA molecule in vivo can generate a double-stranded siNA molecule with 3'-terminal overhangs, such as 3'-terminal nucleotide overhangs comprising about 2 nucleotides. Modified nucleotides present in siNA molecules, preferably in the antisense strand of the siNA molecules, but also optionally in the sense and/or both antisense and sense strands, comprise modified nucleotides having properties or characteristics similar to naturally occurring ribonucleotides. For example, the invention features siNA molecules including modified nucleotides having a Northern conformation (e.g., Northern pseudorotation cycle, see for example Saenger, Principles of Nucleic Acid Structure, Springer-Verlag ed., 1984). As such, chemically modified nucleotides present in the siNA molecules of the invention, preferably in the antisense strand of the siNA molecules of the invention, but also optionally in the sense and/or both antisense and sense strands, are resistant to nuclease degradation while at the same time maintaining the capacity to mediate RNAi. Non-limiting examples of nucleotides having a northern configuration include locked nucleic acid (LNA) nucleotides (e.g., 2'-O, 4'-C-methylene-(D-ribofuranosyl) nucleotides); 2'-methoxyethoxy (MOE) nucleotides; 2'-methyl-thio-ethyl, 2'-deoxy-2'-fluoro nucleotides. 2'-deoxy-2'- chloro nucleotides, 2'-azido nucleotides, and 2'-O-methyl nucleotides. The sense strand of a double stranded siNA molecule may have a terminal cap moiety such as an inverted pfeoxybasic moiety, at the 3'-end, 5'-end, or both 3' and 5'-ends of the sense strand. Non-limiting examples of conjugates include conjugates and ligands described in Vargeese et al., U.S. Application Serial No. 10/427,160, filed April 30, 2003, incorporated by reference herein in its entirety, including the drawings. In another embodiment, the conjugate is covalently attached to the chemically-modified siNA molecule via a biodegradable linker. In one embodiment, the conjugate molecule is attached at the 3'-end of either the sense strand, the antisense strand, or both strands of the chemically-modified siNA molecule. In another embodiment, the conjugate molecule is attached at the 5'-end of either the sense strand, the antisense strand, or both strands of the chemicallymodified siNA molecule. In yet another embodiment, the conjugate molecule is attached both the 3'-end and 5'-end of either the sense strand, the antisense strand, or both strands of the chemically-modified siNA molecule, or any combination thereof, hi one embodiment, a conjugate molecule of the invention comprises a molecule that facilitates delivery of a chemically-modified siNA molecule into a biological system, such as a cell. In another embodiment, the conjugate molecule attached to the chemically-modified siNA molecule is a poly ethylene glycol, human serum albumin, or a ligand for a cellular receptor that can mediate cellular uptake. Examples of specific conjugate molecules contemplated by the instant invention that can be attached to chemically-modified siNA molecules are described in Vargeese et al., U.S. Patent Application Publication No. 20030130186, published July 10, 2003, and U.S. Patent Application Publication No. 20040110296, published June 10, 2004. The type of conjugates used and the extent of conjugation of siNA molecules of the invention can be evaluated for improved pharmacokinetic profiles, bioavailability, and/or stability of siNA constructs while at the same time maintaining the ability of the siNA to mediate RNAi activity. As such, one skilled in the art can screen siNA constructs that are modified with various conjugates to determine whether the siNA conjugate complex possesses improved properties while maintaining the ability to mediate RNAi, for example in animal models as are generally known in the art. A siNA further may be further comprised of a nucleotide, non-nucleotide, or mixed nucleotide/non-nucleotide linker that joins the sense region of the siNA to the antisense region of the siNA. In one embodiment, a nucleotide linker can be a linker of 2 nucleotides in length, for example about 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length. In another embodiment, the nucleotide linker can be a nucleic acid aptamer. By "aptamer" or "nucleic acid aptamer" as used herein is meant a nucleic acid molecule that binds specifically to a target molecule wherein the nucleic acid molecule has sequence that comprises a sequence recognized by the target molecule in its natural setting. Alternately, an aptamer can be a nucleic acid molecule that binds to a target molecule where the target molecule does not naturally bind to a nucleic acid. The target molecule can be any molecule of interest. For example, the aptamer can be used to bind to a ligand-binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein. This is a non-limiting example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art. [See, for example, Gold et al, Annu. Rev. Biochem., 64: 763 (1995); Brody and Gold, J. Biotechnol., 74: 5 (2000); Sun, Curr. Opin. Mol. Ther., 2:100 (2000); Kusser, J. Biotechnol, 74: 27 (2000); Hermann and Patel, Science 287: 820 (2000); and Jayasena, Clinical Chemistry, 45: 1628. (1999) A non-nucleotide linker may be comprised of an abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, polyhydrocarbon, or other polymeric compounds (e.g. polyethylene glycols such as those having between 2 and 100 ethylene glycol units). Specific examples include those described by Seela and Kaiser, Nucleic Acids Res., 18:6353 (1990) and Nucleic Acids Res., 15:3113 (1987); Cload and Schepartz, J. Am. Chem. Soc., 113:6324 (1991); Richardson and Schepartz, J. Am. Chem. Soc., 113:5109 (1991); Ma et al., Nucleic Acids Res., 21:2585 (1993) and Biochemistry 32:1751(1993); Durand et al., Nucleic Acids Res., 18:6353 (1990); McCurdy et al., Nucleosides & Nucleotides, 10:287 (1991); Jschke et al., Tetrahedron Lett., 34:301 (1993); Ono et al., Biochemistry, 30:9914 (1991); Arnold et al., International Publication No. WO 89/02439; Usman et al., International Publication No. WO 95/06731; Dudycz et al., International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc., 113:4000 (1991). A "non-nucleotide" further means any group or compound that can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound can be abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymidine, for example at the Cl position of the sugar. The synthesis of a siNA molecule of the invention, which can be chemically-modified, comprises: (a) synthesis of two complementary strands of the siNA molecule; (b) annealing the two complementary strands together under conditions suitable to obtain a double-stranded siNA molecule. In another embodiment, synthesis of the two complementary strands of the siNA molecule is by solid phase oligonucleotide synthesis, hi yet another embodiment, synthesis of the two complementary strands of the siNA molecule is by solid phase tandem oligonucleotide synthesis. Oligonucleotides (e.g., certain modified oligonucleotides or portions of oligonucleotides lacking onucleotides) are synthesized using protocols known in the art, for example as described in Caruthers et al., 1992, Methods in Enzymology 211, 3-19, Thompson et al., International PCT Publication No. WO 99/54459, Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al., 1997, Methods Mol. Bio., 74, 59, Brennan et al., 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, U.S. Pat. No. 6,001,311. Synthesis of RNA, including certain siNA molecules of the invention, follows general procedures as described, for example, in Usman et al., 1987, J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990, Nucleic Acids Res., 18, 5433; and Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684 Wincott et al., 1997, Methods Mol. Bio., 74, 59. Supplemental or complementary methods for delivery of nucleic acid molecules for use within then invention are described, for example, in Akhtar et al., Trends Cell Bio., 2, 139 (1992); Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995, Maurer et al., Mol. Membr. Biol., 16: 129-140 (1999); Hofland and Huang, Handb. Exp. Pharmacol., 137: 165-192 (1999); and Lee et al., ACS Symp. Ser., 752: 184-192 (2000). Sullivan et al., International PCT Publication No WO 94/02595, further describes general methods for delivery of enzymatic nucleic acid molecules. These protocols can be utilized to supplement or complement delivery of virtually any nucleic acid molecule contemplated within the invention. Pharmaceutical Compositions Nucleic acid molecules and polynucleotide delivery-enhancing polypeptides can be administered to cells by a variety of methods known to those of skill in the art, including, but not restricted to, administration within formulations that comprise the siNA and polynucleotide delivery-enhancing polypeptide alone, or that further comprise one or more additional components, such as a pharmaceutically acceptable carrier, diluent, excipient, adjuvant, emulsifier, buffer, stabilizer, preservative, and the like. In certain embodiments, the siNA and/or the polynucleotide delivery-enhancing polypeptide can be encapsulated in liposomes, administered by iontophoresis, or incorporated into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, bioadhesive microspheres, or proteinaceous vectors (see e.g., O'Hare and Normand, International PCT Publication No. WO 00/53722). Alternatively, a nucleic acid/peptide/vehicle combination can be locally delivered by direct injection or by use of an infusion pump. Direct injection of the nucleic acid molecules of the invention, whether subcutaneous, intramuscular, or intradermal, can take place using standard needle and syringe methodologies, or by needle-free technologies such as those described in Conry et al., Clin. Cancer Res., 5: 2330-2337 (1999) and Barry et al., International PCT Publication No. WO 99/31262. The compositions of the instant invention can be effectively employed as pharmaceutical agents. Pharmaceutical agents prevent, modulate the occurrence or severity of, or treat (alleviate one or more symptom(s) to a detectable or measurable extent) of a disease state or other adverse condition in a patient. Thus within additional embodiments the invention provides pharmaceutical compositions and methods featuring the presence or administration of one or more polynucleic acid(s), typically one or more siNAs, combined, complexed, or conjugated with a polynucleotide delivery-enhancing polypeptide, optionally formulated with a pharmaceutically-acceptable carrier, such as a diluent, stabilizer, buffer, and the like. The present invention satisfies additional objects and advantages by providing short interfering nucleic acid (siNA) molecules that modulate expression of genes associated with a particular disease state or other adverse condition in a subject. Typically, the siNA will target a gene that is expressed at an elevated level as a causal or contributing factor associated with the subject disease state or adverse condition. In this context, the siNA will effectively downregulate expression of the gene to levels that prevent, alleviate, or reduce the severity or recurrence of one or more associated disease symptoms. Alternatively, for various distinct disease models where expression of the target gene is not necessarily elevated as a consequence or sequel of disease or other adverse condition, down regulation of the target gene will nonetheless result in a therapeutic result by lowering gene expression (i.e., to reduce levels of a selected mRNA and/or protein product of the target gene). Alternatively, siNAs of the invention may be targeted to lower expression of one gene, which can result in upregulation of a "downstream" gene whose expression is negatively regulated by a product or activity of the target gene. Within exemplary embodiments, the compositions and methods of the invention are useful as therapeutic tools to regulate expression of tumor necrosis factor-a (TNF-a) to treat or prevent symptoms of rheumatoid arthritis (RA). In this context the invention further provides compounds, compositions, and methods useful for modulating expression and activity of TNF- a by RNA interference (RNAi) using small nucleic acid molecules. In more detailed embodiments, the invention provides small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (mRNA), and short hairpin RNA (shRNA) molecules, and related methods, that are effective for modulating expression of TNF-a and/or TNF-a genes to prevent or alleviate symptoms of RA in mammalian subjects. Within these and related therapeutic compositions and methods, me use of chemically-modified siNAs will often improve properties of the modified siNAs in comparison to properties of native siNA molecules, for example by providing increased resistance to nuclease degradation in vivo, and/or through improved cellular uptake. As can be readily determined according to the disclosure herein, useful siNAs having multiple chemical modifications will retain their RNAi activity. The siNA molecules of the instant invention thus provide useful reagents and methods for a variety of therapeutic, diagnostic, target validation, genomic discovery, genetic engineering, and pharmacogenomic applications. This siNAs of the present invention may be administered in any form, for example transdermally or by local injection (e.g., local injection at sites of psoriatic plaques to treat psoriasis, or into the joints of patients afflicted with psoriatic arthritis or RA). In more detailed embodiments, the invention provides formulations and methods to administer therapeutically effective amounts of siNAs directed against of a mRNA of TNF-a, which effectively downregulate the TNF- a RNA and thereby reduce or prevent one or more TNF-a-associated inflammatory condition(s). Comparable methods and compositions are provided that target expression of one or more different genes associated with a selected disease condition in animal subjects, including any of a large number of genes whose expression is known to be aberrantly increased as a causal or contributing factor associated with the selected disease condition. The siNA/polynucleotide delivery-enhancing polypeptide mixtures of the invention can be administered in conjunction with other standard treatments for a targeted disease condition, for example in conjunction with therapeutic agents effective against inflammatory diseases, such as RA or psoriasis. Examples of combinatorially useful and effective agents in this context include non-steroidal antiinflammatory drugs (NSAIDs), methotrexate, gold compounds, D-penicillamine, the antimalarials, sulfasalazine, glucocorticoids, and other TNF-a neutralizing agents such as infliximab and entracept. Negatively charged polynucleotides of the invention (e.g., RNA or DNA) can be administered to a patient by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for formation of liposomes can be followed. The compositions of the present invention may also be formulated and used as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions for injectable administration, and the other compositions known in the art. The present invention also includes pharmaceutically acceptable formulations of the compositions described herein. These formulations include salts of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid. A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., systemic administration, into a cell or patient, including for example a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the negatively charged nucleic acid is desirable for delivery). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity. By "systemic administration" is meant in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Administration routes which lead to systemic absorption include, without limitation: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes exposes the desired negatively charged polymers, e.g., nucleic acids, to an accessible diseased tissue. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation that can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach may provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as cancer cells. By "pharmaceutically acceptable formulation" is meant, a composition or formulation that allows for the effective distribution of the nucleic acid molecules of the instant invention in the physical location most suitable for their desired activity. Nonlimiting examples of agents suitable for formulation with the nucleic acid molecules of the instant invention include: P-glycoprotein inhibitors (such as Pluronic P85), which can enhance entry of drugs into the CNS [Jolliet-Riant and Tillement, Fundam. Clin. Pharmacol., 13:16-26 (1999)]; biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after intracerebral implantation (Emerich, D F et a/., Cell Transplant, 8: 47-58 (1999)] (Alkermes, Inc. Cambridge, Mass.); and loaded nanoparticles, such as those made of polybutylcyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms (Prog Neuropsychopharmacol Biol Psychiatry, 23: 941-949, (1999)]. Other non-limiting examples of delivery strategies for the nucleic acid molecules of the instant invention include material described in Boado et al., J. Pharm. Sci., 87:1308-1315 (1998); Tyler et al., FEES Lett, 421: 280-284 (1999); Pardridge et al., PNAS USA., 92: 5592-5596 (1995); Boado, Adv. Drug Delivery Rev., 15: 73-107 (1995); Aldrian-Herrada et al., Nucleic Acids Res., 26: 4910-4916 (1998); and Tyler et al., PNAS USA, 96: 7053-7058 (1999). The present invention also includes compositions prepared for storage or administration, which include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). For example, preservatives, stabilizers, dyes and flavoring agents may be provided. These include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. In addition, antioxidants and suspending agents may be used. A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence of, or treat (alleviate a symptom to some extent, preferably all of the symptoms) a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors that those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present. Pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, ratty acids such as oleic acid find use in the preparation of injectables. The siNAs can also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. The siNAs can be modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'-fluoro, 2'-O-methyl, 2'-H. [For a review see Usman and Cedergren, TIBS 17: 34 (1992); Usman et al., Nucleic Acids Symp. Ser. 31: 163 (1994)]. SiNA constructs can be purified by gel electrophoresis using general methods or can be purified by high pressure liquid chromatography and re-suspended in water. Chemically synthesizing nucleic acid molecules with modifications (base, sugar and/or phosphate) can prevent their degradation by serum ribonucleases, which can increase their potency. See e.g., Eckstein et al., International Publication No. WO 92/07065; Perrault et al., Nature 344: 565 (1990); Pieken et al., Science 253, 314 (1991); Usman and Cedergren, Trends in Biochem. Sci. 17: 334 (1992); Usman et al., International Publication No. WO 93/15187; and Rossi et al., International Publication No. WO 91/03162; Sproat, U.S. Pat. No. 5,334,711; Gold et al., U.S. Pat. No. 6,300,074. All of the above references describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of the nucleic acid molecules described herein. There are several examples in the art describing sugar, base and phosphate modifications that can be introduced into nucleic acid molecules with significant enhancement in their nuclease stability and efficacy. For example, oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'-fluoro, 2'-O-methyl, 2'-O-allyl, 2'-H, nucleotide base modifications. For a review see Usman and Cedergren, , TIBS. 17: 34 (1992); Usman et al., Nucleic Acids Symp. Ser. 31:163 (1994); Burgin et al., Biochemistry, 35: 14090 (1996). Sugar modification of nucleic acid molecules have been extensively described in the art. See Eckstein et al., International Publication PCT No. WO 92/07065; Perrault et al. Nature,344, 565-568 (1990); Pieken et al. Science, 253: 314-317 (1991); Usman and Cedergren, Trends in Biochem. Sci., 17: 334-339 (1992); Usman et al. International Publication PCT No. WO 93/15187; Sproat, U.S. Pat. No. 5,334,711 and Beigelman et al., 1995, J. Biol. Chem., 270, 25702; Beigelman et al., International PCT publication No. WO 97/26270; Beigelman et al., U.S. Pat. No. 5,716,824; Usman et al., U.S. Pat. No. 5,627,053; Woolf et al., International PCT Publication No. WO 98/13526; Thompson et al., Karpeisky et al., Tetrahedron Lett., 39: 1131 (1998); Earnshaw and Gait, Biopolymers (Nucleic Acid Sciences, 48: 39-55 (1998); Verma and Eckstein, Annu. Rev. Biochem., 67: 99-134 (1998); and Burlina et al., Bioorg. Med. Chem., 5: 1999-2010 (1997). Such publications describe general methods and strategies to determine the location of incorporation of sugar, base and/or phosphate modifications and the like into nucleic acid molecules without modulating catalysis. In view of such teachings, similar modifications can be used as described herein to modify the siNA nucleic acid molecules of the instant invention so long as the ability of siNA to promote RNAi in cells is not significantly inhibited. While chemical modification of oligonucleotide internucleotide linkages with phosphorothioate, phosphorodithioate, and/or 5'-methylphosphonate linkages improves stability, excessive modifications can cause some toxicity or decreased activity. Therefore, when designing nucleic acid molecules, the amount of these internucleotide linkages should be minimized. The reduction in the concentration of these linkages should lower toxicity, resulting in increased efficacy and higher specificity of these molecules. In one embodiment, the invention features modified siNA molecules, with phosphate backbone modifications comprising one or more phosphorothioate, phosphorodithioate, methylphosphonate, phosphotriester, morpholino, amidate carbamate, carboxymethyl, acetamidate, polyamide, sulfonate, sulfonamide, sulfamate, formacetal, thioformacetal, and/or alkylsilyl, substitutions. For a review of oligonucleotide backbone modifications, see Hunziker and Leumann, Nucleic Acid Analogues: Synthesis and Properties, in Modern Synthetic Methods, VCH, 331-417 (1995), and Mesmaeker et al., Novel Backbone Replacements for Oligonucleotides, in Carbohydrate Modifications in Antisense Research, ACS, 24-39 (1994). Methods for the delivery of nucleic acid molecules are described in Akhtar et al., Trends Cell Bio., 2: 139 (1992); Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, (1995), Maurer et al., Mol. Membr. Biol., 16: 129-140 (1999); Hofland and Huang, Handb. Exp. Pharmacol., 137: 165-192 (1999); and Lee et al., ACS Symp. Ser., 752: 184-192 (2000). Beigelman et al., U.S. Pat. No. 6,395,713 and Sullivan et al., PCT WO 94/02595 further describe the general methods for delivery of nucleic acid molecules. These protocols can be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules can be administered to cells by a TOriety of methods known to those of skill in the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as biodegradable polymers, hydrogels, cyclodextrins (see for example Gonzalez et al., Bioconjugate Chem., 10: 1068-1074 (1999); Wang et al., International PCT publication Nos. WO 03/47518 and WO 03/46185), poly(lactic-co-glycolic)ac- id (PLGA) and PLCA microspheres (see for example U.S. Pat. No. 6,447,796 and US Patent Application Publication No. US 2002130430), biodegradable nanocapsules, and bioadhesive microspheres, or by proteinaceous vectors (O'Hare and Normand, International PCT Publication No. WO 00/53722). Alternatively, the nucleic acid/vehicle combination is locally delivered by direct injection or by use of an infusion pump. Direct injection of the nucleic acid molecules of the invention, whether subcutaneous, intramuscular, or intradermal, can take place using standard needle and syringe methodologies, or by needle-free technologies such as those described in Conry et al., Clin. Cancer Res., 5: 2330-2337 (1999) and Barry et al., International PCT Publication No. WO 99/31262. The molecules of the instant invention can be used as pharmaceutical agents. Pharmaceutical agents prevent, modulate the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a subject. In this specification and the appended claims, the singular forms of "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. EXAMPLES Example 1 Production and Characterization of Compositions Comprising a siRNA Complexed With a Polynucleotide Delivery-Enhancing Polypeptide To form complexes between candidate siRNAs and polynucleotide delivery-enhancing polypeptides of the invention, an adequate amount of siRNA is combined with a pre-determined amount of polynucleotide deliveryenhancing polypeptide, for example in Opti-MEM® cell medium (Invitrogen), in defined ratios and incubated at room temperature for about 10-30 min. Subsequently a selected volume, e.g., about 50 ul, of this mixture is brought into contact with target cells and the cells are incubated for a predetermined incubation period, which in the present example was about 2 hr. The siRNA/peptide mixture can optionally include cell culture medium or other additives such as fetal bovine serum. For H3, H4 and H2b, a series of experiments was performed to complex these polynucleotide delivery-enhancing polypeptides with siRNA in different ratios. Generally this was initiated with a 1:0.01 to 1:50 of siRNA/histone ratio. To each well in a 96-well microtiter plate, 40 pm siRNA was added. Each well contained beta-gal cells at 50% confluency. Exemplary optimized ratios for transfection efficiency are shown in Table 2 below. Transfections were performed with either regular siRNA or siRNA complexed with one of the aboveidentified histone proteins on 9L/beta-gal cells. The siRNA was designed to specifically knock down betagalactosidase mRNA, and activities are expressed as percentage of beta-gal activities from control (control cells were transfected using lipofectamine without the polynucleotide delivery-enhancing polypeptide). Assays for detecting and/or quantifying the efficiency of siRNA delivery are carried out using conventional methods, for example beta-galactosidase assay or flow cytometry methods. For beta-galactosidase assays, 9L/LacZ cells, a cell line constitutively expressing beta-galactosidase, were used. 9L/LacZ cells are rat gliosarcoma fibroblast cells that constitutively express LacZ and were obtained from ATCC (#CRL-2200). 9L/LacZ cells were grown in Dulbecco's Modified Essential Medium (DMEM) media with a supplement of 1 mM sodium pyruvate, nonessential amino acids, and 20% fetal bovine serum. Cells were cultured at 37°C and 5% CO2 supplemented with an antibiotic mixture containing 100 units/ml penicillin, 100 n.g/ml streptomycin and 0.25 mg/ml Fungizone (Invitrogen). The siRNA duplex designed against beta-gal mRNA was chemically synthesized and used with delivery reagents to evaluate knock-down efficiency. siRNA Synthesis and Preparation Synthesis of oligonucleotides was carried out using the standard 2-cyanoethyl phosphoramidite method on long chain alkylamine controlled pore glass derivatized with 5'-O-Dimethyltrityl-2'-O-/-butyldimethylsilyl-3'-6- succinyl ribonucleoside of choice or 5'-O-Dimethyltrityl-2'-deoxy-3'-O-succinyl thymidine support where applicable. All oligonucleotides were synthesized at either the 0.2 or 1-umol scale using an ABI 3400 DNA/RNA synthesizer, cleaved from the solid support using concentrated NH4OH, and deprotected using a 3:1 mixture of NHjOH : EtOH at 55 °C. The deprotection of 2'-TBDMS protecting groups was achieved by incubating the base-deprotected RNA with a ablution (600 |LiL per rnol) of N-methylpyrrolidone/triethylamine/triethylamine tris(hydrofluoride) (6:3:4 by volume) at 65 °C for 2.5 hours. The corresponding building blocks, 5'-dimethoxytrityl-A-(tac)-2'-O-(/-butyldimethylsilyl)-3'- [(2-cyanoethyl)-(A,Ar-diisopropyl)]-phosphoramidites of A, U, C and G (Proligo, Boulder CO) as well the modified phosphoramidites, 5'DMTr-5-methyl-U-TOM-CE-Phosphoramidite, 5'-DMTr-2'-OMe-Ac-C-CE Phosphoramidite, 5'- DMTr-2'-OMe-G-CE Phosphoramidite, 5'-DMTr-2'-OMe-U-CE Phosphoramidite, 5'-DMTr-2'-OMe-A-CE Phosphoramidite (Glen Research) were purchased directly from suppliers. Triethylamine-trihydrofluride, Nmethylpyrrolidinone and concentrated ammonium hydroxide was purchased from Aldrich. All HPLC analysis and purifications were performed on a Waters 2690 with Xterra™ columns. All other reagents were purchased from Glen Research Inc. Oligonucleotides were purified to greater than 97% purity as determined by RP-HPLC. siRNAs for mouse injection were purchased from Qiagen, which were HPLC purified after annealing with acceptable endotoxin level for in vivo injection. Transfection Procedure On the first day of the procedure, saturated 9L/LacZ cultures are taken from T75 flasks, and the cells are detached and diluted into 10ml of complete medium (DMEM, IxPS, IxNa Pyruvate, Ix NEAA). The cells are further diluted to 1:15, and lOOul of this preparation are aliquoted into wells of 96 well plates, which will generally yield about 50% cell confluence by the next day for the transfection. Edges of the wells are left empty and filled with 250 ul water, and the plates are placed un-stacked in the incubator overnight at 37°C (5% CO2 incubator). On the second day, the transfection complex is prepared in Opti-MEM, 50ul each well. The medium is removed from the plates, and the wells are washed once with 200ul PBS or Opti-MEM. The plates are blotted and dried completely with tissue by inversion. The transfection mixture is then added (50ul/well) into each well, and 250ul water is added to the wells on the edge to prevent them from drying. The cells are then incubated for at least 3 hours at 37°C (5% CO2 incubator). The transfection mixture is removed and replaced with lOOul of complete medium (DMEM, IxPS, IxNa Pyruvate, Ix NEAA). The cells are cultured for a defined length of time, and then harvested for the enzyme assay. The siRNA sequence used to silence the beta-galactosidase mRNA was the following: C.U.A.C.A.C.A.A.A.U.C.A.G.C.G.A.U.U.U.dT.dT (Sense) (SEQ ID NO: 32) A.A.A.U.C.G.C.U.G.A.U.U.U.G.U.G.U.A.G.dT.dT (Antisense) (SEQ ID NO: 33) The data for the present example is shown in Table 2. The transfection efficiency inversely correlates with the amount of beta-galactosidase activity measured from the cell lysate. Upon transfection, a measured decrease in beta-galactosidase activity indicates a successful transfection. Thus, in the absence of transfection, the measured beta-galactosidase activity is 100% and the transfection efficiency is 0%. As beta-galactosidase activity decreases, the transfection efficiency increases. For example, in Table 2, Histone H2B plus siRNA results in a transfection efficiency of 62.03% indicating that the measured beta-galactosidase activity decreased to 37.97%. The same approach for determining transfection efficiency was used for the data presented in Table 3. To evaluate the effects of adding a cationic lipid to a siRNA/polynucleotide delivery-enhancing polypeptide mixture, complex or conjugate, the above procedures were followed except the lipofectamine (Invitrogen) was added to siRNA/polynucleotide delivery formulation in constant concentrations, following manufacturer's instructions (0 2 ul/lOOulOpti-MEM). To produce the composition comprised of GKINLKALAALAKKIL (SEQ ID NO: 28), siRNA and LIPOFECTIN® (Invitrogen), the siRNA and peptide were mixed together first in Opti-MEM cell culture medium at room temperature, after which LIPOFECTIN® was added at room temperature to the mixture to form the siRNA/peptide/cationic lipid composition. To produce the composition comprised of RVIRVWFQNKRCKDKK (SEQ ID NO: 29), siRNA and LIPOFECTIN*, the peptide and the LIPOFECTIN® were mixed together first in Opti-MEM cell culture medium, into this mixture was added the siRNA to form the siRNA/peptide/LIPOFECTIN® composition To produce the siRNA/peptide/cationic lipid composition using GRKKRRQRRRPPQGRKKRRQRRRPPQGRKKRRQRRRPPQ (SEQ ID NO: 30) or GEQIAQLIAGYIDIILKKKKSK (SEQ ID NO: 31) it does not matter in which order the components are added together to produce the siRNA/peptide/cationic lipid composition. To produce the siRNA/mellitin/LIPOFECTIN®, the siRNA and mellitin were first mixed together in Opti- MEM cell culture medium and then the LIPOFECTIN® was added to the mixture. To produce the siRNA/histone HI /LIPOFECTIN® composition, the histone HI and LIPOFECTIN® were first added together in Opti-MEM cell culture medium thoroughly mixed and then the siRNA was added, thoroughly and mixed with the histone LIPOFECTIN® mixture to form the siRNA/histone HI/ LIPOFECTIN® composition. Based on the foregoing results, it is apparent that exemplary polynucleotide delivery-enhancing polypeptides of the invention can substantially enhance cellular uptake of siRNAs, while the addition of an optional cationic lipid to certain siRNA/polypeptide mixtures of the invention may substantially improve siRNA delivery efficiency. Example 2 Production and Characterization of Compositions Comprising a siRNA Conjugated With a TAT-HA Polynucleotide Delivery-Enhancing Polvpeptide The present example describes the synthesis and uptake activity of specific peptides covalently conjugated to one strand of a siRNA duplex. These conjugates efficiently deliver siRNA into the cytoplasm. Both peptides and RNAs are prepared using standard solid phase synthesis methods. To form conjugates, the peptide and RNA molecules must be functionalized with specific moieties to allow for covalent attachment to each other. For the peptide, the N-terminus is functionalized with 3-maleimidopropionic acid. For the RNA molecule the 5' end of the sense strand or 3' end of the antisense strand is functionalized with a l-Odimethoxytrityl- hexyl-disulfide linker using standard procedures. Structure of the peptide-siRNA conjugate (SEQ ID NOS 34 and 35) Cells were plated the day before so that they were ~50-80% confluent at time of transfection. For complexes, siRNA and peptide were diluted in Opti-MEM® media (Invitrogen), then mixed and allowed to complex 5-10 minutes before adding to cells washed with PBS. Final concentration of siRNA was SOOnM at each peptide concentration (2- SOM). The conjugate, also diluted in Opti-MEM® media, was added to cells at final concentrations ranging from 62.5nM to SOOnM. At SOOnM concentration, we also combined with 20% FBS just before adding to washed cells. Cells were transfected for 3 hours at 37°C, 5%CO2. Cells were washed with PBS, treated with trypsin and then analyzed by flow cytometry. siRNA uptake was measured by intensity of Cy5 fluorescence and cellular viability assessed by addition of propidium iodide. As shown in Figure 1, the peptide/siRNA conjugates achieve a greater percent uptake in mouse tail fibroblast cells than peptide/siRNA complexes. Further, the peptide/siRNA conjugates achieved a higher mean fluorescence intensity (MFI; Figure 2) than the peptide/siRNA complex. Thus, these data indicate that in certain embodiments it will be desirable to conjugate the polynucleotide delivery-enhancing polypeptide to the siRNA molecule. Example 3 Screening of siRN A/Delivery Peptide Complexes for siRNA Uptake in 9L/LacZ Cells The present example provides additional evidence that a broad and diverse assemblage of rationally-designed polynucleotide delivery-enhancing polypeptides of the invention enhance siRNA uptake when complexed with siRNAs. Uptake was measured using 9L/lacZ cells transfected as described in Example 2. Cells were washed with PBS, treated with trypsin and then analyzed by flow cytometry. siRNA uptake was measured by intensity of FAM fluorescence and cellular viability assessed by addition of propidium iodide. Table 4 below summarizes the percent cell uptake data in 9L/LacZ cells for the various rationally-designed polynucleotide delivery-enhancing polypeptides. Included in this table, is the concentration of the peptide and siRNA used. Example 4 SiRN A/Deli very is Enhanced by Polynucleotide Delivery-Enhancing Polypeptides In Vitro The present example illustrates the enhancement of siRNA uptake by polynucleotide delivery-enhancing polypeptides of the invention in LacZ cells, murine primary fibroblasts and human monocytes. The materials and methods used for the experiments performed in 9L/LacZ cells and mouse fibroblast cells are generally the same as described above, except that for the murine experiments, 9L/LacZ cells were replaced with mouse tail fibroblasts. The results for transfections performed with mouse tail fibroblast (MTF) cells are summarized in Table 5, which shows the concentration of the peptide and siRNA used along with the label conjugated to the siRNA molecule. The results for transfections performed with both MTF and 9L/LacZ cells are summarized in Table 6. The data presented in Table 6 compares transfection efficiencies for some peptide/siRNA complexes in different cell types. NH2-RRRQRRKRGGDIMGEWGNEIFGAIAGFLG-amide (SEQ ID NO: 35) NH2- KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQamide (SEQ ID NO: 59) Peg- KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQamide (SEQ ID NO: 90) NH2- RGSRRAVTRAQRRDGRRRRRSRRESYSVYVYRVLRQamide( SEQIDNO:91) NH2-KKDGKKRKRSRKESYSVYVYKVLKQ-amide (SEQ ID NO: 58) AAVALLPAVLLALLAPRKKRRQRRRPPQC (SEQ ID NO: 38) NH2-RQIKIWFQNRRMKWKK-amide (SEQ ID NO: 53) NH2-RVIRWFQNKRCKDKK amide (SEQ ID NO: 67) Maleimido-RVIRWFQNKRSKDKK-amide (SEQ ID NO: 92) Maleimide-WRFKQqQqQqQqQq-amide (SEQ ID NO: 76) NH2-RKKRRQRRRPPQCAAVALLPAVLLALLAP-amide (SEQ ID NO: 39) GRKKRRQRRRPPQC (SEQ ID NO: 36) KLALKLALKALKAALKLA-amide (SEQ ID NO: 13) NH2-GWTLNSAGYLLGKINLKALAALAKKIL-amide NH2-AAVALLPAVLLALLAPRKKRRQRRRPPQ-amide (SEQ ID NO: 94) NH2-RKKRRQRRRPPQAAVALLPAVLLALLAP-amide (SEQ ID NO: 89) NH2-AAVALLPAVLLALLAPSGASGLDKRDYV-amide (SEQ ID NO: 47) NH2-RQIKIWFQNRRMKWKK-amide (SEQ ID NO: 53) NH2-SGRGKQGGKARAKAKTRSSRAGLQFPVGRVHRLLRKGC-amide (SEQ ID NO: 56) NH2-KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ-amide (SEQ ID NO: 59) NH2-RVIRWFQNKRCKDKK-amide (SEQ ID NO: 67) NH2-GRKKRRQRRRPPQC-amide (SEQ ID NO: 36) NH2-KETWWETWWTEWSQPKKKRKV-amide (SEQ ID NO: 95) NH2-LLETLLKPFQCRICMRNFSTRQARRNHRRRHRR-amide (SEQ ID NO: 50) NH2-C(YGRKKRRQRRRG)2-amide (SEQ ID NO: 42) NH2-RRRQRRKRGGDIMGEWGNEIFGAIAGFLG-amide (SEQ ID NO: 35) NH2-KKDGKKRKRSRKESYSVYVYKVLKQ-amide (SEQ ID NO: 58) NH2-AAVALLPAVLLALLAPRRRRRR-amide (SEQ ID NO: 45) NH2-RGSRRAVTRAQRRDGRRRRRSRRESYSVYVYRVLRQ-amide (SEQ ID NO: 91) NH2-GALFLGFLGAAGSTMGAWSQPKSKRKVC-amide (SEQ ID NO: 96) Peg-KGSKJCAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ-amide To further characterize the ability of polynucleotide delivery-enhancing polypeptides to transfect cells in culture, human monocytes were incubated with FITC labeled siRNA complexed with various concentrations of PN73, PN250, PN182, PN58 and PN158. Human monocytes were used in addition to LacZ and mouse fibroblast cells because they are the targeted cell type in the treatment of rheumatoid arthritis. Monocytes were isolated from fresh human blood samples from healthy donors, to a purity greater than 95% by FACS analysis. Monocytes were transfected using procedures of Example 2 using Cy5- or FAM-conjugated siRNA and peptide, and siRNA uptake was measured by the intensity of intracellular Cy5 or FAM fluorescence. Cell viability was determined using propidium iodide (uptake) or AnnexinV-PE (staining). Figure 3 illustrates the ability of several different polynucleotide delivery-enhancing polypeptides to enhance siRNA uptake in human monocytes in culture. Transfection by lipofectamine was used as a comparator. Cell viability was also assessed for each peptide. The results showed that the polynucleotide delivery-enhancing polypeptide, PN73 is an ideal candidate for the treatment of rheumatoid arthritis. The data show the surprising and unexpected discovery that the PN73 peptide enhances uptake of siRNA by human monocytes with high efficiency and low toxicity indicating that suggests it can be used for the treatment of rheumatoid arthritis in vivo. Example 5 siRNA/Deliverv is Enhanced by peptide-siRNA Conjugates The present example provides results from screens to evaluate activity of siRNA/polynucleotide deliveryenhancing polypeptide conjugates for inducing or enhancing siRNA uptake in 9L/LacZ culture cell lines and primary fibroblast from mouse tail. The results for transfections performed with 9L/LacZ cells are summarized in Table 7. The results for transfections performed with MTF are summarized in Table 8. of siRNA uptake mediated by rationally-designed polynucleotide delivery-enhancing polypeptides conjugated to siRNAs in LacZ cells Efficiency of siRNA uptake mediated by rationally-designed polynucleotide delivery-enhancing polypeptides conjugated to siRNAs in murine tail fibroblast cells Maleimide-RRRQRRKRGGDMGEWGNEIFGAIAGFLGamide (SEQ ID NO: 102) Maleimide- KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQamide (SEQ ID NO: 103) Maleimide- AAVALLPAVLLALLAPRKKRRQRRRPPQamide (SEQ ID NO: 37) Maleimide-Dmt-r-FKQqQqQqQqQq-amide (SEQ ID NO: 74) Maleimide-RQIKIWFQNRRMKWKK-amide (SEQ ID NO: Maleimido-KETWWETWWTEWSQPKKKRKV-amide (SEQ ID NO: 104) Maleimido-RVIRWFQNKRSKDKK-amide (SEQ ID NO: 92) Maleimide-WRFKQqQqQqQqQq-amide (SEQ ID NO: 76) Maleimide- RKKRRQRRRPPQCAAVALLPAVLLALLAPamide (SEQ ID NO: 105) NH2-WRFKC-amide (SEQ ID NO: 106) Maleimide-GRKKRRQRRRPPQ-amide (SEQ ID NO: 43) Maleimido-KLALKLALKALKAALKLA-amide (SEQ ID NO: 107) Maleimido-GWTLNSAGYLLGKINLKALAALAKKILamide (SEQ ID NO: 108) The foregoing data evince that a diverse assemblage of siRNA/peptide conjugates of the invention mediate delivery of siRNAs into different cell types at high efficiency. Example 6 9 siRNA Gene Expression Knock Down is Enhanced by Polvnucleotide Delivery-Enhancing Polvpeptides Complexed to siRNA The instant example demonstrates effective knockdown of target gene expression by siRNA/polynucleotide delivery-enhancing polypeptide complexes of the invention. In the current studies, the ability of peptide/siRNA complexes to modulate expression of a human tumor necrosis factor-a (hTNF-a) gene, implicated as mediating the occurrence or progression of RA when overexpressed in human and other mammalian subjects, was tested. Human monocytes were isolated and transfected as described in Example 4. For mRNA measurement, branch DNA technology from Genospectra (CA) was used according to manufacturer's specification. Human monocytes (CD 14+) treated with LPS induce TNF-a-specific mRNA within approximately 2 hrs, followed by peak levels of TNFa protein 2 hrs later. siRNAs were screened for knockdown activity by transfecting monocytes with siRNA candidate sequences using Lipofectamine 2000, treating infected cells with LPS, and measuring TNF-a mRNA levels approximately 16 hrs later. Various siRNA sequences were screened (Table 9) for their ability to knockdown TNF-a mRNA and protein levels in activated human primary monocytes. To quantitate mRNA level in the cells, both house keeping gene (cypB) and target gene (TNF-a) mRNA were measured, and the reading for TNF- a was normalized with cypB to obtain relative luminescence unit. To quantify protein level, the TNF-a ELISA from BD Bioscience was used according to manufacturer's specification. Table 10, 11 and 12 illustrate the effectiveness of specific oligos complexed to a polynucleotide deliveryenhancing polypeptides of the invention to target and knock down TNF-a gene expression levels in human monocytes. Activities for a representative set of siRNA sequences ranged from 80% mRNA knockdown activity to no detectable activity. In general, TNF-a protein levels were reduced more than mRNA levels, e.g., a 50% knockdown in TNF-a mRNA (TNF-a-1) resulted in a 75% reduction in TNF-a protein level. Dose response curves for selected exhibited knockdown levels from 30% to 60 % were obtained. Calculated IC50values were in the 10 olar to 200 pMolar range. While the siRNA sequences evaluated were distributed throughout the TNF-a transcript, the most potent siRNAs identified were located in two areas: the middle of the coding region and the 3'-UTR. The foregoing results (Tables 10, 11 and 12) evince that effective levels of TNF-a gene expression knock down can be achieved in mammalian cells using the novel siRNA/polynucleotide delivery-enhancing polypeptide compositions of the invention. Example 7 siRNA Gene Expression Knock Down is Enhanced by Polynucleotide Delivery-Enhancing Polypeptides Conjugated with siRNA The present example demonstrates knockdown of target gene expression by peptide-siRNA conjugates of the invention. The materials and methods for these studies are the same as those described above . The results of this example are illustrated in Table 13. The results show that a diverse assemblage of polynucleotide delivery-enhancing polypeptides of the invention conjugated with siRNAs function to enhance siRNA-mediated knockdown of TNF- gene expression in mammalian subjects. Example 8 Time Course of siRNA Gene Expression Knock Down The instant example presents studies relating to the time course of siRNA-mediated gene expression Knockdown. To test the duration of the siRNA effect, the siRNA transfection procedures as noted above were employed, except that fibroblasts derived from eGFP expressing mice were used. The transfection reagent used here was lipofectamine. The cells were replated on the 18th day due to overgrowth. The second transfection was performed on the 19th day post first transfection. On the 19th day the eGFP levels were measured after the transfection. Scramble or nonsense siRNA (Qiagen) was used as a control, along with a GFPI siRNA (GFPI) and a hairpin siRNA (D#21). The knockdown activities were calibrated with scramble siRNA (Qiagen control) Table 14: Time Course of EGFP Gene Expression Knock Down by Lipofectamine Mediated Transfection The foregoing studies (Table 14) demonstrate that siRNA knockdown activity became apparent around day 3, and was sustained through day 9, whereafter target gene expression returned to baseline levels around day 17. After the second transfection on day 18, another reduction of eGFP expression occurred indicating that the reagent can be repeatedly administered to cells to yield repeated or enduring gene expression knockdown. Example 9 Multiple Dosing Protocol to Extend siRNA Knockdown Effect in Mammalian Cells The instant example demonstrates that multiple dosing schedules will effectively extend gene expression knockdown effects in mammalian cells mediated by siRNA/polynucleotide delivery-enhancing polypeptide compositions of the invention. The materials and methods employed for these studies are the same as described above, with the exception that repeated transfections were conducted at the times indicated. The scramble siRNA (Qiagen) was utilized for side by side controls. Table 15 summarizes the data for multiple transfections with a peptide/siRNA complex. The percent knockdown activity of the TNF-a gene represents the percent of total gene expression. The foregoing results demonstrate that when multiple transfections are performed timely (in this case between about the 5th-7th day post first transfection), TNF-a gene expression knockdown effects in mammalian cells can be maintained or re-induced. Example 10 Optimizing Rational Design of Polvnucleotide Delivery-Enhancing Polvpeptides The instant example provides an exemplary design and data for optimizing polynucleotide delivery-enhancing polypeptides of the invention. The subject rational design manipulations were conducted for a histone H2B-derived polynucleotide delivery-enhancing polypeptide. In order to better understand the function-structural activity relationships of this and other polynucleotide delivery-enhancing polypeptides, primary structural studies were performed by characterizing C- and N-terminal function, and activity of conjugates between PN73 and other chemical moieties. The amino acid sequence for the human histone 2B (H2B) protein is shown below. PN73, PN360 and PN361 are peptide fragments of H2B and the portion of the H2B protein that they represent are identified below in parentheses following the peptide name. The amino acids sequence for PN360 and PN361 listed below are aligned with the corresponding amino acid sequence found in PN73. The PN73 peptide fragment is underlined in the H2B amino acid sequence and represents H2B amino acids 13 through 48. It may also be represented by H2B amino acids 12 through 48. PN360 shares the N-terminus with PN73 but lacks PN73's C-terminus while PN361 shares the C-terminus with PN73 but lacks PN73's N-terminus. The PN73 conjugate is PN73 covalently linked to a single siRNA strand (e.g., sense strand). PN404 is a version of PN73 in which all of lysines are replaced with arginines and PN509 is a pegylated PN73 (PEG molecular weight Ik Dalton ) derivative that is pegylated at the Nterminus. H2B (histone 2B) amino acid sequence MPEPAKSAPAPKXGSKKAVTKAOKKDSKKRKRSRKESYSVYVYKVLKV HPDTGISSKAMGMNSFYNDIFERIAGEASRLAHYNKRSTITSREIQTAVRL LLPGELAKHAVSEGTKAVTKYTSSK (SEQ ID NO: 164) PN73 (13-48) NH2-KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ-amide (SEQ ID NO: 59) PN360 (13-35; N-terminus of PN73) NH2-KGSKKAVTKAQKKDGKKRKRSRK-amide (SEQ ID NO: 57) PN361 (24-48; C-terminus of PN73) NH2-KKDGKKRKRSRKESYSVYVYKVLKQ-amide (SEQ ID NO: 58) PN73 (13-48)-siRNA (sense strand) conjugates siRNA-KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ-amide (SEQ ID NO 59) PN404 (PN73 where all lysines are replaced with arginines) NH2-RGSRRAVTRAQRRDGRRRRRSRRESYSVYVYRVLRQ-amide(SEQ ID NO: 91) PN509 (pegylated PN73) PEG- RGSRRAVTRAQRRDGRRRRRSRRESYSVYVYRVLRQ-amide (SEQ ID NO: 59). Figure 5 provides the results of uptake efficacy and viability studies in mouse tail fibroblast cells for the foregoing PN73 rationally-designed derivative polynucleotide delivery-enhancing polypeptides. The activity changes of modified PN73 in mouse tail fibroblast cells are illustrated. Unlike PN404, PN509 increases uptake without increasing toxicity. While deleting part of the N-terminus of PN73 reduces activity, removal of C-terminal residues abolishes the activity. Both PN73 and PN509 show higher activity in primary cells than Lipofectamine (Invitrogen, Example 11 Acetylated Polynucleotide Delivery-Enhancing Polypeptide Increases siRNA Stability The purpose of the instant example was to determine if modification of the exemplary polynucleotide deliveryenhancing polypeptide PN73 would provide increased stability to the peptide and consequently enhance its transfection activity. The stability of unmodified, N-terminus pegylated and N-terminus acetylated forms of PN73 in plasma was compared. The C-terminus of the PN73 is amidated. Size exclusion chromatography coupled with an ultraviolet detector were used to characterize the stability of the unmodified and modified forms of PN73 before and after incubation in plasma. In the absence of plasma, the unmodified, pegylated and acetylated forms of PN73 showed distinct yet overlapping UV traces at approximately 9 minutes. However, after 4 hours of exposure to plasma, UV traces specific to unmodified PN73 and pegylated PN73 were no longer present indicating significant degradation. In contrast, the distinct UV trace for acetylated PN73 remained indicating that this modification significantly increased stability of the PN73 in plasmid compared to the unmodified and pegylated PN73 forms. These data show the surprisingly and unexpected discovery that PN73 stability in plasma can be enhanced by N-terminus acetylation of the PN73 peptide. The primary structure of the acetylated PN73 peptide is as follows: Ac-KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ-amide (SEQ ID NO: 59) Example 14 Polynucleotide Delivery-Enhancing Polvpeptide Does Not Elicit an Interferon Response The purpose of the instant example was to compare the interferon response of cells transfected with either lipofectamine plus siRNA or the exemplary polynucleotide delivery-enhancing polypeptide, PN73 peptide plus siRNA. Interferon responsiveness was assayed by ELISA (protein) and bDNA (mRNA levels). Traditionally, siRNA molecules are delivered into cells by a liposomal mediated transfection. However, this typically results in a poor efficiency of delivery, an inflammatory response in vivo and an upregulation of interferon gene expression which results in an inhibition of cell growth. Consequently, there is a limited reduction in targeted gene expression levels thus making siRNA an ineffective method of treatment and tool for studying gene expression. Delivery of siRNA by PN73 overcomes this problem. Interferon responsiveness of lipofectamine was compared to PN73 peptide in transfection of several different siRNAs. siRNAs were complexed with either lipofectamine or PN73 at concentrations of 1 nM, 10 nM, 100 nM or 200 nM. Interleukin ip (IL-1P) served as a molecular marker to determine interferon responsiveness and Qneg was used as a negative control. Results showed that lipofectamine complexed with the 100 nM or 200 nM TNF-a9 siRNA caused a significant increase in IL-lp mRNA levels. Furthermore, all other siRNAs tested caused a mild increase in IL-lp mRNA levels. In contrast, the same siRNAs complexed with the PN73 peptide did not cause an increase in IL- 1P mRNA levels. To further characterize the difference in interferon responsiveness observed between cells transfected with either lipofectamine and PN73 transfection, an ELISA assay was performed to determine the protein expression levels of the following molecular markers: Interleukin ip (IL-lp), Interferon-ct (INF-ct), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-12 (IL-12), MEP-la, Interferon-y (IFN-y), and Tumor Necrosis Factor-a (TNF-a). Table 16 summarizes the relative protein expression levels of cells transfected with lipofectamine complexed with siRNA or PN73 complexed with siRNA. The results showed both siRNA LC20 and LCI7 had no interferon response regardless of what transfection rfttgent was used. However, transfection of EFN-1 or TNF-a9 with lipofectamine caused an increase in IL-1J3, IL-6, and MlP-la, protein expression levels. In contrast, transfection of all tested siRNAs with PN73 caused no observable induction in protein expression in any of the interferon response markers tested. These data from the ELISA assay show the surprisingly and unexpected discovery that PN73 mediated transfection of siRNAs does not elicit an interferon response. Example 15 siRNA Conjugated with a Polvnucleotide Delivery-Enhancing Polypeptide Provides Greater Knockdown Activity than siRNA Complexed with Polynucleotide Delivery-Enhancing Polypeptide. The purpose of the instant example was to compare the knockdown activities in human monocytes of the siRNAs LCI3 and LC20 either conjugated or complexed with the exemplary polynucleotide delivery-enhancing polypeptide PN73. Isolation and transfection of human monocytes as well as the methods used to measure knockdown activity were discussed earlier. Qneg represents a random siRNA sequence and functions as the negative control in these experiments. The observed Qneg knockdown activity is normalized to 100% (100% gene expression levels) and the activity of LC20 and LCI3 is presented as a relative percentage of the negative control. LC20 and LCI3 are siRNAs targeted against the human TNF-a gene. The knockdown activity for the siRNAs LC20 and LCI3 without PN73, in a complex with PN73 or conjugated with PN73 were tested over a concentration range of 0 nM to 2.5 nM. PN73 was kept at a 1:1 ratio in both the complex and conjugate experiments. In the absence of PN73, LCI3 and L20 showed little knockdown activity (Figure 6-C). Both LCI3 and LC20 caused an approximate 15% and 30% decrease in TNF-a gene expression relative to the Qneg control when complexed with PN73 (Figure 6-B). However, knockdown activity for TNF-a was reduced to below 60% when the siRNA was conjugated to PN73 (Figure 6-A). This is significant increase the siRNA knockdown activity compared to the PN73/siRNA complex. Thus, these data show the surprisingly and unexpected discovery that siRNA knockdown activity is significantly enhanced when the siRNA is conjugated to the exemplary polynucleotide delivery-enhancing polypeptide PN73. Example 16 Deletion Analysis of the Exemplary Polynucleotide Delivery-Enhancing Polypeptide The purpose of the present example was to determine the minimum length of the PN73 peptide that is critical for its ability to enhance the delivery of small and macromolecules into cells. A shown in Table 17,10 truncated forms of PN73 were created by sequentially deleting 3 residues at a time from the N-terminus of the peptide. Below is an explanation of the primary structure of PN73 and the truncated forms that will be examined for transfection activity. All peptides tested in this Example were tagged with a C-terminus FITC (fluorescein-5-isothiocyanate) label (i.e., -GK[EPSILON]G-amide). Table 17: PN643 or PN73 (13-48) KGSKJCAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 59) PN661 (16-48) KXAVTKJ\QKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 165) PN685 (19-48) VTKAQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 166) PN660 (22-48) AQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 167) PN735 (25-48) KDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 168) PN655 (28-48) KKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 169) PN654 (31 -48) KRSRKESYSVYVYKVLKQ (SEQ ED NO: 170) PN708 (34-48) RKESYSVYVYKVLKQ (SEQ ID NO: 171) PN653 (37-48) SYSVYVYKVLKQ (SEQ ID NO: 172) PN652 (40-48) VYVYKVLKQ (SEQ ID NO: 173) PN651 (43-48) YKVLKQ (SEQ ID NO: 174) Example 17 In Vivo siRNA-Mediated Gene Expression Knock Down Activity A. eGFP mice r 37- eGFP transgenic mice, 20-25g body weight, were purchased from Jackson Laboratory. For siRNA injections, was used at a dose of 5mg/kg at a 1:5 ratio of siRNA/PN73. All treatments were by tail vein injections once daily for three days. The tissues were clollected on day 4. The experimental protocols were performed at R&R Rabbitary (Standwood, WA) and approved by their Institutional Animal Care and Use Committee (IACUC). The tissues from animal were placed in PBS immediately and stored on ice. For isolation cells from tissues, the sample tissues were placed between 2 frosted glass microscope slides with frosted side facing tissue. Smear together to mash tissue several times. Then rinse off the smashed tissue from slides into the well of 12-well plate with PBS. One ml of mashed tissue was transferred to 12-well plate containing 1 ml of 2X collagenase (type I for muscle and II for liver tissue); the final concentration is 100 units/ml. Incubation of tissues in collagenase solution for 3 hours at 37°C; In order to remove the small pieces and connective tissue, filter the digested tissue mixture through cell strainer into 6 well plate. Transfer 500 ul cells into labeled FACS tubes. Fluorescence intensity of the isolated cells was determined by flow cytometry. A double stranded siRNA duplex specific against eGFP were chemically synthesized. siRNA was dissolved either in PBS buffer or saline or glucose buffer. The three groups of animals (specific eGFP siRNA alone, peptide/eGFP siRNA complex and control siRNA/peptide complex) were iv injected in varied doses and durations as indicated in Table 1. The peripheral blood of treated mice was drawn through orbital bleeding and stored on ice in the presence of anticoagulant. The PBMC were isolated by Ficoll based centrifugation method. And the knockdown activities were assessed by determining the eGFP fluorescent intensity in the cells by flow cytometry Reduction of eGFP protein in muscle cells in EGFP transgenic animal Transgenic mice were treated with siRNA in eGFP transgenic mouse complexed with peptide PN73 (1:5 ratio) (5 mg/kg for three days). For determination of the knockdown activities, cells were isolated from muscle tissue following treatment with collagenase as mentioned in methods section. The fluorescence intensity of isolated cells were analyzed by flow cytomethry. In comparison with control siRNA and GFP siRNA alone, GFP siRNA/PN509 (pegylated PN73) complex showed effective knockdown of EGFP in vivo after consecutive three day injections. Reduction of eGFP protein and niRNA in liver cells in EGFP transgenic animal Transgenic mice were treated with siRNA in eGFP transgenic mouse complexed with peptide PN73 (1:5 ratio) (5 mg/kg for three days). For determination of the knockdown activities, cells were isolated from liver tissue following treatment with collagenase as mentioned in methods section. The fluorescence intensity of isolated cells were analyzed by flow cytomethry. In comparison with control siRNA/PN602 and GFP siRNA alone, GFP siRNA/PN509 (pegylated PN73) complex showed effective knockdown of EGFP in vivo after consecutive three day injections. Knockdown of eGFP mRNA are here summarized in Table 18.. Knockdown of protein expression is comparable. The delivery peptide can efficiently delivery siRNA and knockdown eGFP in PBMC in vivo (up to 50%). In comparison with negative control, naked siRNA also showed some activity in knocking down of eGFP, but it is much less efficient. B. Taconic Mice For human TNF-a animal disease models, two transgenic models were used. The tg!97 mice were acquired from Pasteur Hellenic Institute (Athens, Greece), and the B6.SJL-Tg(TNF) N21 mice were purchased from Taconic, Inc. (Germantown, NY). The genotypes of both human TNF-a transgenic mouse models were performed by suppliers. For tg!97 mice, 6-week old mice were divided into three treatment groups for infliximab, siRNA/PN73 complex and saline. Infliximab, a TNF-a neutralizing antibody based drug, was purchased from a local drug store (as Remicade) and used at a dose of 10 mg/kg, once per week. siRNA was used at a dose of 2mg/kg at a 1:5 ratio of siRNA/PN73. All treatments were by tail vein injection twice a week. The experimental protocols were performed at SkeleTech Inc. (Bothell, WA) and approved by their Institutional Animal Care and Use Committee (IACUC). A similar dose regimen was used for B6.SJL-Tg(TNF) N21 mice. Clinical scores were based on a previously described scoring system (2, 3) as follows: 0 (normal), 1 (edema or distortion of paw or ankle joints), 2 (distortion of paw and ankle joints), or 3 (ankylosis of wrist or ankle joints). The sum of all four paws was scored twice a week with a maximum score of 12 per mouse. For determination of TNF-a level, For the analysis of experiments involving transgenic mice, plasma samples were separated from whole blood collected by orbital bleeding. Plasma levels of hTNF-a were determined by ELISA at a 1:2 dilution according to the manufacturer's instructions (R&D systems, Minneapolis, MN). bDNA assays (Quantigene assay from Genospectra, Fremont, CA) were performed following the manufacturer's instructions. Reduction of human TNF-a plasma protein level and RA scores in transgenic mice after treatment with siRNA/PN73 complex or infliximab. Human TNF-a transgenic mice were treated starting on 5 weeks of age with infliximab (10|xg/kg, ip injection) and siRNA (LC20) against TNF-a complexed with peptide PN73 (1:5 ratio) (2 mg/kg, iv injection, twice weekly). For Hellenic transgenic mice, RA scores were determined (blinded to treatment) using the following criteria: 0, normal; 1, edema or distortion of paw or ankle joints; 2 distortion of paw and ankle joints; 3, ankylosis of wrist or ankle joints. The LC20/PN73 treated group show dramatic suppression of clinic progressions of joint arthritis during three week treatment period. Reduction of human TNF-a plasma protein level after treatment with siRNA/PN73 complex or infliximab For Taconic mice, TNF-a levels in plasma were determined by ELISA (R&D systems, Minneapolis, MN) and treatment schedules were same as Hellenic transgenic hTNF-a transgenic mice. C. Helenic Mice The present example provides in vivo data demonstrating the efficacy of siRNA/polynucleotide deliveryenhancing polypeptide compositions of the invention to mediate systemic delivery and therapeutic gene knockdown by siRNA, effective to modulate target gene expression and modify phenotype of cells in a therapeutic manner. Human NF-a expressing mice were purchase from the Hellenic Pasture Institute, Greece) at 5weeks old. Mice were administered through intra venous (IV) with 300ul saline twice a week (4 mice), with the RA drug Ramicade (5mg/kg) once a week (2 mice), or with LC20 siRNA (2mg/kg) mixed with PN73 at 1:5 molar ratio twice a week (2 mice). During the injection periods, plasma samples were collected for ELISA testing (R&D Systems, Cat#SSTAOOC), and paw scores were taken twice a week as an accepted index of RA disease progression and therapeutic efficacy (Table 19). The foregoing results demonstrate effective reduction of TNF-a protein levels in peptide/siRNA-treated mice ill the circulating blood as compared to levels in Ramicade or saline (control) treated mice. Additional evidence of in vivo efficacy of the siRNA/polynucleotide delivery-enhancing polypeptide compositions and methods of the invention were obtained from the above murine subjects using paw scores, an accepted phenotypic index for RA disease status and treatment efficacy. Due to the difference in the starting point (some animals present with scores at earlier points), the scores have been adjusted to 0 for all animals in the experiments. Each paw is given a score between 0 and 3, with the highest score of 12, according to the following scoring index. 0: Normal 1: edema or distortion of paw or ankle joints 2: distortion of paw and ankle joints 3: ankylosis of wrist or ankle joints. The results of these paw score evaluations are presented graphically in Figure 4. The data demonstrate that the polynucleotide delivery-enhancing polypeptide PN73 can deliver therapeutic amounts of siRNAs (e.g. LC20, TNF-a2, and TNF-a9 (UAGCCCAUGUUGUAGCAAA (SEQ ID NO. 175))) when injected into animals as shown by a delayed RA progression at week 8. The PN73/siRNA treated mice faired better on the paw scoring index at week 8 compared to the Ramicade-treated mice. When paw score evaluations were carried out to 11 weeks post-treatment, PN73/LC20 complex achieved comparable paw score evaluations to the Ramicade-treated mice. At a ratio of 1:5 for the PN73 peptide/LC20 siRNA, 2 mg/kg LC20 achieved the greatest relative observed delay in RA progression compared to the lower doses of LC20 tested. Table 20 below summarizes the relative effectiveness of several siRNAs for 5 different groups evaluated after treatment with PN73 and siRNAs. exes LC20, YC12 and LC17 Overall low paw score. YC12 and LC17 not as effective as LC20 LC20, a9 TNF-a2 and TNF- LC20 and TNF-a9 are more effective than Ramicade by week 8; LC20 is equally effective as Ramicade by week 11 'siRNAs were tested in the presence of absence ofPN73; Ramicade is a positive treatment control; PBS is a negative treatment control. The foregoing results demonstrate that siRNA and polynucleotide delivery-enhancing polypeptide compositions of the invention provide promising new therapeutic tools for regulating gene expression and treating and managing disease. siRNAs of the invention, for example siRNAs targeting human TNF-a-specific mRNAs for degradation, offer higher specificity, lower immunogenicity and greater disease modification than current small molecule, soluble receptor, or antibody therapies for RA. More than 50 candidate siRNA sequences were screened that targeted hTNF-a and yielded single administration knockdowns of 30-85%. Over 20 in silica designed peptide complex and/or covalent molecules were compared for fluorescent RNA uptake by monocytes and a number were found to have significantly better uptake than Lipofectamine or cholesterol-conjugated siRNA and with 10 pM IC50 values. The peptide-siRNA formulations efficiently knockdown TNF-a mRNA and protein levels in activated human monocytes in vitro. One exemplary candidate delivery peptide/siRNA formulation was evaluated in two transgenic mouse models or rheumatoid arthritis (RA) constitutively expressing human TNF-a. Animals treated with 2 mg/kg siRNA by FV injection or infliximab twice weekly beginning at age 6 weeks showed RA score stabilization (paw and joint inflammation) beginning at age 7 weeks, compared to controls where these disease conditions persisted through week 10. At age 9 weeks, siRNA treated animals showed comparable reductions in RA scores, but significantly lower plasma TNF-a protein levels than infliximab treated animals. Based on the disclosure herein, the use of siRNA to inhibit the expression of target genes, for example cytokines such as TNF-a, that play important roles in pathological states, such as inflammation, provides effective treatments to alleviate or prevent symptoms of disease, as exemplified by RA, in mammalian subjects. Exemplary peptide/siRNA compositions employed within the methods and compositions of the invention provide advantages relating to their ability to reduce or eliminate target gene expression, e.g., TNF-a expression, rather than by complexing with the product of the target gene, e.g., TNF-a, as in the case of antibodies or soluble receptors. Improving systemic delivery of nucleic acids according to the teachings of the invention provides yet additional advantages for development of siRNAs as drugs. Specific challenges in this context include delivery through tissue barriers to a target cell or tissue, maintaining the stability of the siRNA, and intracellular delivery getting siRNAs across cell membranes into cells in sufficient quantities to be effective. The present disclosure demonstrates for the first time an effective in vivo delivery system comprising novel peptide/siRNA compositions targeting specific gene expression, such as expression of human TNF-a, which attenuate disease activity in transgenic animal models predictive of target diseases, as exemplified by studies using murine models of RA. In related studies, the compositions and methods of the invention effectively inhibit TNF-a expression in activated monocytes derived from patients with RA. These results indicate that the RNAi pathway effectively mediates alteration of cellular phenotype and disease progression through intracellular effects on TNF-pathways, and avoids toxicity effects due to circulating antibody/TNF-a complexes with residual immunoreactivity that characterize current antibody therapies for RA. Notably, all of the tests herein were implemented with associated toxicity effects minimized, such that the dosages of siNAs and polynucleotide delivery-enhancing polypeptides shown in these examples always correlated with cell viability levels of at least 80-90% or greater. D. Mouse LPS Response Normal [mouse type] mice were treated with various concentrations of LPS by intraperitoneal or intravenous injections. LPS responsiveness was determined by measuring levels of TNF-a in blood that was sampled various times following the LPS injection. A linear range of TNF-a induction was found between 10 ng and 100 ng for LPS injection by IP administration and up to 25 ng by IV injection. The average time for maximal TNF-a induction is 70 minutes following LPS injection. On the basis of these results, the following LPS doses were selected for further experimentation: 25 ng for IP administration; 10 ng for IV administration. The effects of siRNA on LPS induction of TNF-a were tested by injection, six mice per treatment schedule, with a 2 mg/kg siRNA dose of (1) LC13/PN73; (2) LC13 alone; (3) Qneg/PN73; (4) PN73; (5) buffer alone. The LPS induction was performed 24 hr following the last siRNA injection, 0.2 ug LPS and blood was collected at 90 minutes following LPS injection. Results (below) indicate that LCI3 (samples 1 and 2) lowered amounts of circulating TNF-a resulting from LPS induction compared to negative controls (samples 3-5). A second experimental approach was utilized using a 2 mg/kg siRNA dose of the following compositions (1) LC13/PN73; (2) Inm-2/PN73; (3) Inm-4/PN73; (4) Qneg/PN73; and (5) PBS (Buffer control). Three studies of 30 animals each dosing by the following schedules: 4 consecutive days; 8 consecutive days; and 11 consecutive days. LPS induction was performed at 24 hr post siRNA injection, 25 ng LPS (IP). Blood was drawn 70 minutes following LPS injection. The results showed that Inm-4 showed greatest KD activity in 4 consecutive day experiment (n=l test) compared to LCI3, Inm-2, and Qneg. Results from measurements and 8 and 11 days gave variable results owing to technical problems partly arising from repeated tail injections. Although the foregoing invention has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to the artisan that certain changes and modifications may be practiced within the scope of the appended claims which are presented by way of illustration not limitation. In this context, various publications and other references have been cited within the foregoing disclosure for economy of description. Each of these references is incorporated herein by reference in its entirety for all purposes. It is noted, however, that the various publications discussed herein are incorporated solely for their disclosure prior to the filing date of the present application, and the inventors reserve the right to antedate such disclosure by virtue of prior invention. We claim: 1. A double stranded ribonucleic acid (dsRNA), comprising a first strand having a ribonucleic acid sequence that is complementary to a tumor necrosis factor-α (TNF-α) mRNA having the nucleotide sequence of SEQ ID NO: 132, useful for inhibiting the production of tumor necrosis factor-α (TNF-α). 2. The double stranded ribonucleic acid (dsRNA) as claimed in claim 1, wherein the first strand has a ribonucleic acid sequence that is complementary to a nucleotide sequence selected from the group consisting of: AAUCGGCCCGACUAUCUCGACUU (SEQ ID NO: 117); AAUGGCGUGGAGCUGAGAGAU (SEQ ID NO: 118); AACCUCCUCUCUGCCAUCAAG (SEQ ID NO: 119); AACUGAAAGCAUGAUCCGGGA (SEQ ID NO: 120); AAUCUCGACUUUGCCGAGUCU (SEQ ID NO: 121); AAGGGUGACCGACUCAGCGCU (SEQ ID NO: 122); AAUCAGCCGCAUCGCCGUCUC (SEQ ID NO: 123); AACCCAUGUGCUCCUCACCCA (SEQ ID NO: 124); AAGCUCCAGUGGCUGAACCGC (SEQ ID NO: 125); AAGUCAGAUCAUCUUCUCGAA (SEQ ID NO: 126); AAGGGACCUCUCUCUAAUCAG (SEQ ID NO: 127); CCUCAGCCUCUUCUCCUUCCUGA (SEQ ID NO: 128); AAUCCUCAGCCUCUUCUCCUU (SEQ ID NO: 129); AACCAAUGCCCUCCUGGCCAA (SEQ ID NO: 130); CUGAUUAAGUUGUCUAAACAA (SEQ ID NO: 131); CCGACUCAGCGCUGAGAUCAA (SEQ ID NO: 132); CUUGUGAUUAUUUAUUAUUUA (SEQ ID NO: 133); AAGCCUGUAGCCCAUGUUGUA (SEQ ID NO: 134); UAGGGUCGGAACCCAAGCUUA (SEQ ID NO: 135); and GCCUGUACCUCAUCUACUC (SEQ ID NO: 147). 3. A double stranded ribonucleic acid (dsRNA) substantially as herein described with reference to foregoing description, examples, tables and drawings.

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