AAV mediated delivery of IL-4 prevents collagen-induced arthritis
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KeywordsRheumatoid Arthritis Gene Therapy Intramuscular Injection Autoimmune Inflammatory Disease LacZ Expression
Immunomodulation of autoimmune inflammatory diseases like rheumatoid arthritis can be achieved by anti-inflammatory T2 cytokines such as interleukin (IL)-4 administered by gene therapy. Engineered cells secreting cytokines was the first demonstrated efficient gene therapy in animals models of arthritis. Adeno-associated virus (AAV) are new gene therapy vectors exhibiting a number of advantages over the others vectors. AAV is a small DNA virus of the Parvoviridae family. In human populations, the overwhelming majority of individuals have been exposed to the AAV, which doesn't seem to have known pathological effects. In addition to being safe, AAV vectors can infect a broad spectrum of host cells, at any phase of their division cycle. Furthermore, recombinant AAV vectors contain no viral genes but only the transgene flanked by two inverting terminal repeats (ITRs), which could package moderately sized transgenes, such as those encoding for cytokines.
We recently investigated the efficiency of adeno-associated virus (AAV) vectors in collagen-induced arthritis (CIA). After injection of AAV-lacZ in the tarsus area of mice, the expression of the transgene was localized in the deep muscle cells near the bone. LacZ expression was found in liver, heart and lung after intramuscular injection of AAV-LacZ, showing a spread of the vector over the body. Anti-AAV neutralizing antibodies were detected in the serum after intramuscular injection of AAV-LacZ, but they didn't alter the transgene expression after re-administration of AAV-LacZ. Long-term IL-4 expression persisted 129 days after intramuscular injection of 3.7 × 1010 or 11.2 × 1010 AAV-IL-4 pp (average 7.7 or 17.5 pgIL-4/mg proteins, respectively). More importantly, the treatment of CIA with AAV-IL-4 vector in mice produced a therapeutic benefit, since we show a diminished prevalence of the disease, a significant reduction in paw swelling, attenuated histological synovitis and a 10 day delayed onset of arthritis. These data show evidence that AAV vector-mediated gene therapy using a T2 cytokine is efficient in an animal model of rheumatoid arthritis.