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

Rachael A Potter; Ellyn L Peterson; Danielle Griffin; Grace Cooper Olson; Sarah Lewis; Kyle Cochran; Jerry R Mendell; Louise R Rodino-Klapac

doi:10.1016/j.omtm.2024.101195

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

Mol Ther Methods Clin Dev. 2024 Jan 23;32(1):101195. doi: 10.1016/j.omtm.2024.101195. eCollection 2024 Mar 14.

Authors

Rachael A Potter¹, Ellyn L Peterson¹, Danielle Griffin¹, Grace Cooper Olson¹, Sarah Lewis¹, Kyle Cochran¹, Jerry R Mendell^{2

3}, Louise R Rodino-Klapac^{1

2

3}

Affiliations

¹ Sarepta Therapeutics, Inc., Cambridge, MA 02142, USA.
² Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
³ Department of Pediatrics and Neurology, The Ohio State University, Columbus, OH 43210, USA.

Abstract

Patients with pre-existing immunity to adeno-associated virus (AAV) are currently unable to receive systemic gene transfer therapies. In this nonhuman primate study, we investigated the impact of immunosuppression strategies on gene transfer therapy safety and 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 per 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 or 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 pre-existing immunity.

Keywords: Duchenne muscular dystrophy; adeno-associated virus; antibodies; delandistrogene moxeparvovec; gene therapy; immunosuppression; plasmapheresis; pre-existing antibodies; redosing; safety.