Reduction of Preexisting AAV9 Antibody Titers Before Onasemnogene Abeparvovec Administration in Twins With Spinal Muscular Atrophy

OBJECTIVES: Preexisting immunity to adeno-associated viruses (AAVs) presents a major obstacle to eligibility for gene therapy. METHODS: We determined the feasibility of immunodepletion with therapeutic plasma exchange and rituximab to lower anti-AAV9 antibody (AAV Ab) titers before gene therapy for spinal muscular atrophy (SMA). RESULTS: Twin 21-month-old brothers with SMA presented with AAV9 Ab titers of 1:800, exceeding the limit of 1:50 for eligibility to receive onasemnogene abeparvovec (OA). Because there was a low expectation of spontaneous reduction in Ab titers, they received 11 plasma exchanges and 2 doses of rituximab, leading to their AAV9 Ab titers dropping to the eligibility range for OA. During their OA infusions, despite methylprednisolone pretreatment, both twins experienced acute hypersensitivity reactions characterized by urticaria, wheezing, and GI disturbances that resolved with epinephrine. The limited dose of OA they received did not lead to marked clinical improvement. DISCUSSION: Therapeutic plasma exchange and rituximab successfully reduced the AAV Ab titers to the range of eligibility, but this regimen combined with corticosteroids was not sufficient to prevent infusion reactions to AAV gene therapy in our patients with preexisting AAV Abs. Further studies are needed to define a protocol that could enable patients to receive AAV-based gene therapy in the presence of preexisting immunity.