Reduction of pre-existing AAV9 antibody titers prior to onasemnogene abeparvovec administration in spinal muscular atrophy

Topic:

Clinical Management

Poster Number: P268

Author(s):

Peter B Kang, MD, University of Minnesota, Ryan Nelson, MD, PhD, University of Minnesota, Cody Cox, MD, University of Oklahoma, Andrew Johnson, MD, University of Minnesota, Molly Stark, DPT, University of Minnesota, Kelly Sichmeller, RN, University of Minnesota Physicians, Jayne Earhart, RN, University of Minnesota Physicians, Jacqueline Ihinger, MS, CGC, Masonic Children's Hospital / M Health Fairview, Seth Stafki, MS, CGC, University of Minnesota, Peter KARACHUNSKI, MD, University of Minnesota

Backgroun: Pre-existing immunity to adeno-associated viruses (AAVs) presents a major obstacle to eligibility for gene therapy. In neonates, antibodies to AAV are typically due to placental transfer and titers spontaneously resolve, whereas the presence of elevated antibody titers in older children indicate a prior infection with the AAV serotype in question. Preclinical data in non-human primates suggest that plasmapheresis may be an effective means of lowering AAV titers in the latter context. We determined the feasibility of immunodepletion prior to gene therapy for spinal muscular atrophy (SMA). Objectives: We report the efficacy and safety of immunodepletion in twin brothers with spinal muscular atrophy with elevated pre-existing AAV9 antibody titers. Results: Twin brothers with SMA were found to have AAV9 antibody titers of 1:800, above the threshold of 1:50 for eligibility to receive onasemnogene abeparvovec. As they were diagnosed with SMA a few months prior to their second birthday with a low expectation of rapid spontaneous reduction in antibody titers, they underwent 11 plasma exchanges and received 2 doses of rituximab, leading to their AAV9 antibody titers dropping to 1:25. They initiated prednisolone and began receiving standard doses of onasemnogene abeparvovec. Ten minutes into the infusions, both twins experienced anaphylactic reactions characterized by wheezing, urticaria, and vomiting that resolved with epinephrine. They received approximately 1/7th of the intended standard dose of onasemnogene abeparvovec. Assessment of their CHOP INTEND and HMFSE scores before and after administration indicated that they did not receive therapeutic benefit from the limited amount of onasemnogene abeparvovec received. Conclusions: Plasmapheresis and rituximab alone may not be sufficient to prepare human immune systems for AAV administration in the setting of pre-existing immunity. Further studies are needed to define a protocol that could fully prepare human immune systems to AAV in the presence of pre-existing antibodies.