Use of plasmapheresis to lower anti-AAV antibodies in nonhuman primates with pre-existing immunity to AAVrh74

Abstract

Patients with preexisting immunity to adeno-associated virus (AAV) are currently unable to receive systemic gene transfer therapies. This nonhuman primate study investigated the impact of immunosuppression strategies on gene transfer therapy safety/efficacy and analyzed plasmapheresis as a potential pretreatment for circumvention of pre-existing immunity or redosing. In Part 1, animals received delandistrogene moxeparvovec (SRP-9001), an AAVrh74-based gene transfer therapy for Duchenne muscular dystrophy. Cohort 1 (control, n=2) received no immunosuppression; cohorts 2-4 (n=3/cohort) received prednisone at different time points; and cohort 5 (n=3) received rituximab, sirolimus, and prednisone before and after dosing. In Part 2, cohorts 2-4 underwent plasmapheresis before redosing; cohort 5 was redosed without plasmapheresis. We analyzed safety, immune response (humoral and cell-mediated responses and complement activation), and vector genome distribution. After 2-3 plasmapheresis exchanges, circulating anti-AAVrh74 antibodies were reduced, and animals were redosed. Plasmapheresis was well tolerated, with no abnormal clinical or immunological observations. Cohort 5 (redosed with high anti-AAVrh74 antibody titers) had hypersensitivity reactions, which were controlled with treatment. These findings suggest that plasmapheresis is a safe and effective method to reduce anti-AAV antibody levels in nonhuman primates prior to gene transfer therapy. The results may inform human studies involving redosing or circumvention of preexisting immunity.