Adeno-associated virus serotype 9 antibody seroprevalence for patients in the United States with spinal muscular atrophy

John W Day; Jerry R Mendell; Arthur H M Burghes; Rudolf W van Olden; Rishi R Adhikary; Keith W Dilly

doi:10.1016/j.omtm.2023.101117

Adeno-associated virus serotype 9 antibody seroprevalence for patients in the United States with spinal muscular atrophy

Mol Ther Methods Clin Dev. 2023 Sep 20:31:101117. doi: 10.1016/j.omtm.2023.101117. eCollection 2023 Dec 14.

Authors

John W Day¹, Jerry R Mendell^{2

3}, Arthur H M Burghes⁴, Rudolf W van Olden⁵, Rishi R Adhikary⁶, Keith W Dilly⁷

Affiliations

¹ Department of Neurology, Stanford University Medical Center, Stanford, CA, USA.
² Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.
³ Department of Pediatrics and Department of Neurology, The Ohio State University, Columbus, OH, USA.
⁴ Department of Neurology and Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, USA.
⁵ Novartis Gene Therapies Switzerland GmbH, Rotkreuz, Switzerland.
⁶ CONEXTS-Real World Evidence, Novartis Healthcare Private Limited, Hyderabad, India.
⁷ Novartis Gene Therapies, Inc., Bannockburn, IL, USA.

Abstract

Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9 (AAV9) vector-based gene therapy for spinal muscular atrophy (SMA). Patients with elevated titers of anti-AAV9 antibodies (AAV9-Ab) should not receive onasemnogene abeparvovec because of potential safety and efficacy implications. We conducted a retrospective study to describe the seroprevalence of anti-AAV9 binding antibodies for pediatric patients with SMA in the United States. At initial testing, 13.0% (115 of 882) of patients (mean [SD] age, 26.29 [33.66] weeks) had elevated AAV9-Ab titers. The prevalence of elevated titers decreased as age increased, with 18.2% (92 of 507) of patients ≤3 months old but only 1.1% (1 of 92) of patients ≥21 months old having elevated titers. This suggests transplacental maternal transfer of antibodies. No patterns of geographic variations in AAV9-Ab prevalence were confirmed. Elevated AAV9-Ab titers in children <6 weeks old decreased in all circumstances. Lower magnitudes of elevated titers declined more rapidly than greater magnitudes. Retesting was completed at the discretion of the treating clinician, so age at testing and time between tests varied. AAV9-Ab retesting should be considered when patients have elevated titers, and elevations at a young age are not a deterrent to eventual onasemnogene abeparvovec administration. Early disease-modifying treatment for SMA leads to optimal outcomes.

Keywords: adeno-associated virus serotype 9; antibody titers; gene therapy; onasemnogene abeparvovec; retrospective analysis; seroprevalence; spinal muscular atrophy.