983. Repeat Intra-Articular Administration of AAV2 Vectors to Rat Joints

• Published in: Molecular therapy Vol. 13; no. S1; p. S378
• Main Authors: Burstein, Haim, Lustig, Kurt, Sandalon, Ziv
• Format: Journal Article
• Language: English
• Published: Milwaukee Elsevier Limited 01-05-2006
• Subjects: Arthritis; Brain; Cell death; Disease; Enzymes; Gene expression; Gene therapy; Genomes; Immune system; Lymphocytes; Viruses
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2006.08.1076

Rheumatoid arthritis is a chronic autoimmune disease characterized by synovial inflammation, leading to the destruction of cartilage and bone. Previously, we demonstrated that a single intra-articular administration of AAV2-TNFR:Fc vector to rats with experimental arthritis resulted in suppression of disease. For treatment of chronic inflammatory arthritis using intra-articular delivery of AAV2-TNFR:Fc vector, intra-articular re-administrations may be required. In this study, we evaluated if serum anti-AAV2 capsid neutralizing antibodies, elicited after intra-articular administration of AAV2-TNFR:Fc vector to rat joints, affect joint transduction following intra-articular re-administration of an AAV2-FlagLuc vector. AAV2-FlagLuc was administered approximately one, three, nine and twelve months after injection of either vehicle or AAV2-TNFR:Fc vector. Two weeks post intra-articular injection of the AAV2-FlagLuc vector, we measured and compared luciferase enzyme activity in joint tissues of vehicle-treated animals with animals treated first with AAV2-ratTNFR:Fc vector.Intra-articular administration of AAV2-TNFR:Fc vector to rat joints elicited serum anti-AAV2 capsid neutralizing antibody response. Following re-administration with AAV2-FlagLuc, the anti- AAV2 capsid neutralizing antibody levels in the serum were up to 10-fold higher compared with those detected prior to vector re-administration. Luciferase enzyme activity, measured following re- administration of AAV2-FlagLuc vector to vehicle-treated animals, was 25-fold higher compared with the assay background in normal joints, and 12-fold higher in inflamed joints. In contrast, luciferase enzyme activity was not detected in normal or arthritic rat joints that were injected first with AAV2-ratTNFR:Fc and then re-administered with AAV2-FlagLuc. However, using RT-PCR analyses, we observed sustained expression of TNFR:Fc for at least 378 days. These results demonstrate that in rats the levels of serum anti-AAV2 capsid neutralizing antibodies, elicited one to twelve months after AAV2 vector administration to the rat joint, are sufficiently high to inhibit transduction following intra-articular re-administration with a vector of the same serotype. The evidence that TNFR:Fc is expressed in the joints for more than a year suggests that frequent repeat administrations to the joints may not be needed.