Background: Gene transfer therapy using systemic adeno-associated virus (AAV) delivery is being extensively investigated for the treatment of monogenic diseases, including Duchenne muscular dystrophy. Clinical development of gene therapy is advancing rapidly, and it is imperative to evaluate strategies to optimize safety and efficacy as well as for dosing individuals with pre-existing antibodies against the vectors used for delivery.
Objectives: The goals of this non-human primate (NHP) study were to 1) investigate the impact of various immunosuppression strategies on the safety and efficacy of gene transfer therapy and 2) analyze the safety and efficacy of Therapeutic Plasma Exchange (TPE) as a potential pre-treatment for individuals with pre-existing immunity.
Results: In the first part of the study, five treatment-naïve NHP cohorts (n=3 each) were dosed at 2×1014 vg/kg titer (supercoiled qPCR titer method) intravenously with rAAVrh74.MHCK7.micro-dystrophin (SRP-9001). Different immunosuppression regimens pre- and post-vector administration were trialed in each cohort. Cohort 1 (control) had no immunosuppression treatment. Cohorts 2–4 were treated with prednisone at different time points (Cohort 2: 1 day pre, 30 days post; Cohort 3: 1 day pre, 60 days post; Cohort 4: 14 days pre, 60 days post), and Cohort 5 was treated with rituximab, sirolimus and prednisone (14 days pre, 60 days post). Transduction and micro-dystrophin expression were analyzed in muscle pre- and post-vector administration. Serum chemistries and immunology were monitored to evaluate safety and immune response.
In the second part of the study, seven of the NHPs dosed in the first part of the study who were positive for AAVrh74 antibodies were treated by TPE prior to a second SRP-9001 dose (prednisone was given 1 day pre, 30 days post). Safety and efficacy were assessed.
Levels of circulating antibodies towards AAVrh74 were reduced after 2–3 consecutive rounds of TPE, and the NHPs were successfully redosed. The procedure was well tolerated with no abnormal clinical or immunological observations. Also, NHPs that underwent TPE demonstrated robust levels of transduction and expression in skeletal muscle, heart and diaphragm.
Conclusions: These findings establish TPE as a safe and efficacious strategy for AAVrh74 vector delivery in NHPs and may inform human studies in individuals with pre-existing immunity, or redosing.
This study was funded by Sarepta Therapeutics, Inc.