Introduction 1 2 3 4 5 6 7 6 8 9 10 11 Gene delivery strategies 12 14 15 16 17 15 18 19 20 Gene transfer vectors Gene transfer vectors can be broadly categorized into two groups: viral and non-viral vectors. In general, viral vectors tend to provide for longer-term gene expression but often come with additional safety concerns, ranging from fears of generating replication competent virus during vector production, random insertion of the transgene into the genome following treatment, or development of a harmful immune response. Plasmid DNA 21 23 24 25 26 27 28 31 32 33 34 35 36 Other non-viral vectors Mycobacterium tuberculosis 37 38 39 Adenovirus 40 41 42 Retrovirus 43 18 44 45 43 Lentivirus 38 46 47 48 49 50 AAV v 5 51 52 54 55 56 57 51 58 59 60 61 62 63 64 65 66 67 Gene transfer strategies IL-1β inhibition 7 60 13 18 17 26 68 69 70 12 15 71 TNF-α inhibition 24 72 25 73 74 62 75 76 77 21 13 IL-18 inhibition 78 Immune deviation 79 80 81 2 82 83 84 2 85 86 86 87 88 63 64 29 89 90 92 93 94 95 31 35 34 14 96 97 30 65 98 27 99 100 101 Promoting apoptosis 102 103 104 105 106 107 108 109 Anti-angiogenesis 110 111 112 113 49 66 48 114 115 116 117 118 Targeting matrix degradation enzymes 119 120 32 121 Targeting NFκB 122 123 124 Other strategies INK4A Cip1 28 33 125 136 1 Table 1 Summary of vectors and genes used in animal models of arthritis   Adenovirus AAV Retrovirus Lentivirus Plasmid DNA Genes demonstrated to successfully treat arthritis in various animal models INK4A CIP1 IL-1ra, sTNFR-Ig, sTNFRI, sTNFR:Fc fusion protein, IL-4, IL-10, angiostatin, IKKβ IL-1ra, sTNFRI variants, IL-4, TGF-β, angiostatin, soluble complement receptor I, superoxide dismutase, catalase Angiostatin, endostatin IL-1ra, sTNFRI receptor variants, sTNFR:Fc fusion protein, sTNFRII, TGF-β, IL-4, IL-10, vIL-10, soluble complement receptor I, TIMP-4, fibronectin peptide, sIL-1RAcP Safety concerns 137 44 Future of gene therapy for arthritis Much progress has been made in the past several years in the use of gene therapy for the treatment of arthritis. However, there are many obstacles that must be overcome in order for it to become a viable treatment option. Future studies will need to address improving targeted delivery of vectors, regulating transgene expression, obtaining long-term transgene expression, and improving the safety and efficacy of the vectors already in use before gene therapy becomes a viable clinical therapy for arthritis. Even in light of the recent setback in clinical trials utilizing AAV vectors, the authors believe that the future of gene transfer for arthritis will rely heavily upon this vector. Once the safety issues have been clarified, these trials can hopefully move forward. Presently, AAV would seem to be the viral vector that has the best profile in terms of safety, efficacy, and level and length of transgene expression. Alternatively, strategies using siRNA technology or preventing the dysregulation of Th17 cells would appear to be emerging as treatment strategies that may one day outperform the current standards of care for rheumatoid arthritis.