| Methods and compositions for lowering the level of tumor necrosis factor (tnf) in tnf-associated disorders -> Monitor Keywords |
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Methods and compositions for lowering the level of tumor necrosis factor (tnf) in tnf-associated disordersRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Whole Live Micro-organism, Cell, Or Virus Containing, Genetically Modified Micro-organism, Cell, Or Virus (e.g., Transformed, Fused, Hybrid, Etc.), Eukaryotic CellMethods and compositions for lowering the level of tumor necrosis factor (tnf) in tnf-associated disorders description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070128177, Methods and compositions for lowering the level of tumor necrosis factor (tnf) in tnf-associated disorders. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 10/314,033, filed on Dec. 6, 2002, which is a continuation of U.S. patent application Ser. No. 09/579,845, filed on May 26, 2000, now U.S. Pat. No. 6,537,540, which claims the benefit of U.S. provisional patent application Ser. No. 60/150,688, filed on May 28, 1999, the contents of each of which are incorporated herein by reference in their entirety. STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH [0002] (Not Applicable) FIELD OF INVENTION [0003] This invention relates to the use of adeno-associated virus (AAV) vectors to lower levels of tumor necrosis factor (TNF). More specifically, the invention relates to AAV vectors encoding a TNF antagonist and methods of using the AAV vectors to reduce the levels of TNF in an individual. BACKGROUND [0004] Tumor necrosis factor-.alpha. (TNF.alpha.) and tumor necrosis factor-.beta. (TNF.beta.) are homologous multifunctional cytokines; the great similarities in structural and functional characteristics of which have resulted in their collective description as tumor necrosis factor or "TNF." Activities generally ascribed to TNF include: release of other cytokines including IL-1, IL-6, GM-CSF, and IL-10, induction of chemokines, increase in adhesion molecules, growth of blood vessels, release of tissue destructive enzymes and activation of T cells. See, for example, Feldmann et al., 1997, Adv. Immunol., 64:283-350, Nawroth et al., 1986, J. Exp. Med., 163:1363-1375; Moser et al., 1989, J. Clin. Invest., 83:444-455; Shingu et al., 1993, Clin. Exp. Immunol. 94:145-149; MacNaul et al., 1992, Matrix Suppl., 1:198-199; and Ahmadzadeh et al., 1990, Clin. Exp. Rheumatol. 8:387-391. All of these activities can serve to enhance an inflammatory response. [0005] TNF initiates its biological effect through its interaction with specific, cell surface receptors on TNF-responsive cells. There are two distinct forms of the cell surface tumor necrosis factor receptor (TNFR), designated p75 (or Type II) and p55 (or Type I) (Smith et al., 1990, Science 248:1019-1023; Loetscher et al., 1990, Cell 61:351-359). TNFR Type I and TNFR Type II each bind to both TNF.alpha. and TNF.beta.. Soluble, truncated versions of the TNFRs with a ligand-binding domain are present in body fluids and joints (Engelmann et al., 1989, J. Biol. Chem. 264:11974-11980; Roux-Lombard et al., 1993, Arthritis Rheum. 36:485-489). [0006] A number of disorders are associated with elevated levels of TNF, many of them of significant medical importance. Among such TNF-associated disorders are congestive heart failure, inflammatory bowel diseases (including Crohn's disease), arthritis and asthma. [0007] TNF appears to effect the heart and endothelium in congestive heart failure and has been implicated in the initiation of an apoptotic process in cardiac myocytes. The role for TNF in this disease is also supported by a temporal association between TNF activation and a transition from asymptomatic to symptomatic congestive heart failure (Ceconi et al., 1998, Prog. Cardiovasc. Dis. 41:25-30). [0008] Inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, are associated with increased expression of TNF (Evans et al., 1997, Aliment. Pharmacol. Ther. 11:1031-1035). Treatment of such disorders have included the widespread use of immunosuppressive agents, such as azathioprine, methotrexate, cyclosporine and glucocorticosteroids (Rutgeerts, 1998, Digestion 59:453-469). [0009] Arthritis is a common crippling condition for which there are no cures and few effective therapies. Approximately one in seven people in the United States are affected by one or more forms of arthritis. Most forms of arthritis are characterized by chronic inflammation of joints resulting from infection, mechanical injury, or immunological disturbance. Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily manifest in the joints by swelling, pain, stiffness, and tissue destruction (Harris, 1990, N. Engl. J. Med, 323:994-996). Systemic manifestations can include elevations in serum levels of acute phase proteins, fever, mild anemia, thrombocytosis, and granulocytosis. In affected joints, there is a synovitis characterized by hyperplasia and inflammation of the synovium with an inflammatory exudate into the joint cavity, leading to erosion of cartilage and bone. [0010] Although rheumatoid arthritis is not directly and imminently life threatening, recent data suggest that RA results in significantly shorter lifespan, and puts an enormous toll on the both the health system, the overall economy due to lost productivity, as well as quality of life resulting from restricted mobility and activities (Schiff, 1997, Am. J. Med., 102(1A):11S-15S). [0011] Current commonly employed therapeutics for treatment of RA fall primarily in three categories: non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and immunosuppressives. NSAIDs are a large group of drugs often used as first line therapy for rheumatoid arthritis. The compounds act primarily through blockade of cyclooxygenase which catalyzes conversion of arachidonic acid to prostaglandins and thromboxanes. As a class, DMARDs, including agents such as gold, sulfasalazine, hydroxychloroquine, and D-penicillamine, are slow acting, quite toxic and there is little evidence that any of these compounds have mitigating effects on the underlying disease. NSAIDs can relieve some of the signs of inflammation and pain associated with arthritis; however, they appear to be ineffective against the immune system and in blocking progression of joint destruction and disease. Immunosuppressive agents, such as corticosteroids and methotrexate, are commonly used in the treatment of RA for suppressing the immune system and thus having an anti-inflammatory effect. However, these agents engender serious systemic toxicity which limits their use and effectiveness. [0012] Although it is widely accepted that RA is an immune-based inflammatory disease, the antigen(s) which trigger the disease remain unknown. This has led to a large number of approaches to therapy under pre-clinical or clinical investigation which involve attempts to modulate the immune response system as a whole. Examples of several general efforts in this direction are highlighted below. [0013] The mechanism of action of NSAIDs has been linked to blocking of cyclooxygenase, an enzyme with both an inducible and a constitutive form. As the inducible form of cyclooxygenase appears to be elevated in inflammatory disease, investigation into compounds selective for the inducible form are underway. In addition, attempts to devise vaccines to treat ongoing arthritis have been made with the use of peptide vaccines directed toward MHC class II or T cell receptor proteins. Generally, it has been proven difficult to demonstrate efficacy of vaccines administered to ongoing disease. [0014] Much of the tissue destruction in RA appears to be due to various metalloproteinases. This group of proteases are believed to be central to the degradation of collagen II and proteoglycan seen in arthritis. A number of inhibitors of various of these enzymes are under pre-clinical or clinical investigation. [0015] A number of broadly immunosuppressive drugs are in clinical testing for use in rheumatoid arthritis, including cyclosporine A and mycophenolate mofetil. As a wide range of cytokines are found in arthritic joints, anti-arthritis therapies have targeted cytokine pathways including those of IL-1, IL-2, IL-4, IL-10, IL-11, TGF.beta., and TNF.alpha., as well as, chemokine pathways (Feldmann et al., 1997). In particular, proinflammatory pathways of IL-1 have been targeted both by attack of IL-1 directly and via the naturally occurring interleukin-1 receptor antagonist molecule. [0016] Methods of administering drug therapy for RA have included, and have been proposed to include, systemic or local delivery of a therapeutic drug and, in the case of proposed gene therapies, of a therapeutic gene. To date, such treatments have fallen short of delivering effective, safe therapy for arthritis for a variety of reasons, including: systemic side effects of many drugs, rapid clearance of therapeutic molecules from injected joints and/or circulation, inefficiency in DNA integration and expression from the genome, limited target cell population associated with some viral delivery vectors, transient gene expression associated with viral vectors which do not readily integrate and induction of an immune response associated with the gene delivery virus. [0017] Use of TNF antagonists, such as soluble TNFRs and anti-TNF antibodies, has shown that a blockade of TNF can reverse effects attributed to TNF including decreases in IL-1, GM-CSF, IL-6, IL-8, adhesion molecules and tissue destruction (Feldmann et al., 1997). Such pleiotropic effects apparently due to the blockade of TNF alone suggests that TNF may lie near the top of the cascade of cytokine mediated events. Elevated levels of TNF-.alpha. are found in the synovial fluid of RA patients (Camussi and Lupia, 1998, Drugs 55:613-620). [0018] The effect of TNF blockade utilizing a hamster anti-mouse TNF antibody was tested in a model of collagen type II arthritis in DBA/1 mice (Williams et al., 1992, Proc. Natl. Acad. Sci. USA, 89:9784-9788). Treatment initiated after the onset of disease resulted in improvement in footpad swelling, clinical score, and histopathology of joint destruction. Other studies have obtained similar results using either antibodies (Thorbecke et al., 1992, Proc. Natl. Acad. Sci. USA, 89:7375-7379) or TNFR constructs (Husby et al., 1988, J. Autoimmun. 1:363-71; Tetta et al., 1990, Ann. Rheum. Dis. 49:665-667; Wooley et al., 1993, J. Immunol. 151:6602-6607; Piguet et al., 1992, Immunology 77:510-514). [0019] Similar results have also been obtained in other animal models of ongoing arthritis. In the rabbit, anti-TNF.alpha. antibody was shown to have an anti-arthritic effect on antigen induced arthritis (Lewthwaite et al., 1995, Ann. Rheum. Dis. 54:366-374). In the rat, anti-TNF therapy has been demonstrated to be effective in adjuvant (Mycobacterium) arthritis (Issekutz et al., 1994, Clin. Exp. Immunol. 97:26-32), in streptococcal cell wall induced arthritis (Schimmer et al., 1997, J. Immunol. 159:4103-4108) and in collagen induced arthritis (Le et al., 1997, Arthritis Rheum. 40:1662-1669). [0020] In the studies described above, the TNF blockade was achieved by systemic delivery of the blocking agent. In a rat collagen arthritis model, delivery of a TNFR gene using an adenoviral vector resulted in transient production of serum levels of TNFR (up to 8 days) and a significant decrease in disease progression when the adenovirus was given to animals undergoing active arthritis (Le et al., 1997). Attempts to deliver the gene directly to the joint were unsuccessful, however, and resulted in an inflammatory reaction to the adenovirus. Continue reading about Methods and compositions for lowering the level of tumor necrosis factor (tnf) in tnf-associated disorders... 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