The present study examines the safety profile of intravenous onasemnogene abeparvovec gene therapy in a real world setting, both alone or in combination with intrathecal antisense oligonucleotide nusinersen therapy in two cohorts of patients with spinal muscular atrophy (SMA). The first cohort included 8 presymptomatic infants treated solely with onasemnogene abeparvovec, while the second cohort comprised 6 symptomatic infants receiving onasemnogene abeparvovec and nusinersen co-therapy. All patients received the corticosteroid prednisolone coincident with gene therapy. Circulating alanine aminotransferase (ALT) and aspartate transaminase (AST) levels were measured to determine potential hepatoxicity, the primary focus of this study. Elevated ALT and AST levels, but no change in GGT levels were observed in 1 pre-symptomatic and 3 symptomatic patients post-treatment. However, all values normalized within three months of onasemnogene abeparvovec injection. Nusinersen treatment received previously or coincident with gene therapy did not impact the elevation of liver transaminases, which was transient. This study highlights the importance of early intervention with molecular treatments for SMA and indicates that prior or coincident treatment with nusinersen is unlikely to impact safety of onasemnogene apoparvovec and could theoretically improve clinical outcomes in symptomatic infants or in those with gene therapy delayed beyond the immediate neonatal period.

K.J.S. was a recipient of a grant from Biogen and received clinical trial funding from AveXis and Biogen. C.R.R.A is a consultant for Biogen. The other authors declare no competing interests.

C.R.R.A. received a fellowship from the MGH ECOR. K.J.S. was funded by NIH NICHD R01HD054599, NIH NINDS R21NS108015, Biogen, and Cure SMA.

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Institutional Ethics Review Board at the Massachusetts General Hospital (protocol 2016P000469) gave ethical approval for this work. Written informed parental consent was obtained from all participants.

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