DMD – ANIMAL MODELS: EP.96 Micro-dystrophin gene therapy delivery and therapeutic plasma exchange in nonhuman primates

Abstract

Gene transfer therapy using systemic adeno-associated virus (AAV) delivery is being studied extensively for the treatment of monogenic diseases, such as Duchenne muscular dystrophy. Gene therapies are advancing rapidly, and it is crucial to optimize safety and efficacy as well as dosing of individuals with pre-existing antibodies against the vectors used for delivery. This nonhuman primate (NHP) study investigated the impact of various immunosuppression strategies on the safety and efficacy of gene transfer therapy and analyzed the safety and efficacy of therapeutic plasma exchange (TPE) as a potential pretreatment for individuals with pre-existing immunity. In part 1 of the study, we intravenously dosed 5 treatment-naive NHP cohorts (n=3 each) with rAAVrh74.MHCK7.micro-dystrophin (SRP-9001). We trialed different immunosuppression regimens pre- and post-vector administration in each cohort. Cohort 1 (control) had no immunosuppression treatment. We treated cohorts 2-4 with prednisone at different time points and cohort 5 with rituximab, sirolimus, and prednisone. We analyzed transduction and micro-dystrophin expression in muscle pre- and post-vector administration. To assess safety and immune response, we monitored serum chemistries and immunology. In part 2, we treated NHPs that were dosed in part 1 and were positive for AAVrh74 antibodies (cohorts 2-4) with TPE prior to a second SRP-9001 dose and assessed safety and efficacy. After 2-3 consecutive rounds of TPE, circulating antibodies toward AAVrh74 were reduced and the NHPs were successfully redosed. The procedure was well tolerated, with no abnormal clinical or immunological observations. Cohort 5 NHPs were redosed at very high levels of circulating antibodies and had hypersensitivity reactions, which were controlled. These findings suggest that TPE in conjunction with AAVrh74 vector delivery is safe and efficacious in NHPs. The results may inform human studies involving redosing or pre-existing immunity.