An Observational Study from Long-Term AAV Re-administration in Two Hemophilia Dogs

摘要: Adeno-associated virus (AAV) vectors have been successfully applied in hemophilia clinical trials. However, this approach is limited to patients without AAV-neutralizing antibodies (NAbs). In study, we explored the feasibility of AAV re-administration A dogs treated initially 8 years ago with AAV8.canine FVIII. After two NAb-negative AAV8 carrying human factor VIII (hFVIII), along proteasome inhibitor bortezomib, observed a phenotypic improvement both that persisted one dog. Phenotypic disappeared at 59 days after other dog, and specific cytotoxic T lymphocytes (CTLs) capsid were detected day 17, but not hFVIII. hFVIII inhibitors 59 gradually increased. Mechanistic studies demonstrated an increase pro-inflammatory cytokines, decrease immunomodulatory as well lower Tregs re-administration. These results suggest development may contribute therapeutic failure via immune response activation. Interestingly, it takes about 30–50 days for NAb titers by half. Collectively, study suggests same serotype long-term follow-up feasible kinetics will provide important information predicating efficacy