Megan A Waldrop1,2, Cassandra Karingada3, Mike A Storey4, Brenna Powers2, Megan A Iammarino2, Natalie F Miller2, Lindsay N Alfano2, Garey Noritz5, Ian Rossman6, Matthew Ginsberg6, Kathryn A Mosher7, Eileen Broomall8, Jessica Goldstein9, Nancy Bass9, Linda P Lowes2, Chang-Yong Tsao10,3, Jerry R Mendell10,2, Anne M Connolly10,2. 1. Departments of Neurology and Pediatrics, The Ohio State University, Columbus, Ohio; megan.waldrop@nationwidechildrens.org. 2. Center for Gene Therapy and. 3. Departments of Neurology and. 4. Pharmacy, Nationwide Children's Hospital, Columbus, Ohio. 5. Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio. 6. Departments of Pediatric Neurology and. 7. Pediatric Physiatry, Akron Children's Hospital, Akron, Ohio. 8. Department of Pediatric Neurology, Cincinnati Children's Hospital, Cincinnati, Ohio; and. 9. Division of Pediatric Neurology, Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio. 10. Departments of Neurology and Pediatrics, The Ohio State University, Columbus, Ohio.
Abstract
BACKGROUND AND OBJECTIVES: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age <2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age ≤8 months. METHODS: In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio. RESULTS: In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. CONCLUSIONS: In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.
BACKGROUND AND OBJECTIVES: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age <2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age ≤8 months. METHODS: In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio. RESULTS: In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. CONCLUSIONS: In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.
Authors: Kevin A Strauss; Michelle A Farrar; Francesco Muntoni; Kayoko Saito; Jerry R Mendell; Laurent Servais; Hugh J McMillan; Richard S Finkel; Kathryn J Swoboda; Jennifer M Kwon; Craig M Zaidman; Claudia A Chiriboga; Susan T Iannaccone; Jena M Krueger; Julie A Parsons; Perry B Shieh; Sarah Kavanagh; Sitra Tauscher-Wisniewski; Bryan E McGill; Thomas A Macek Journal: Nat Med Date: 2022-06-17 Impact factor: 87.241
Authors: Jerry R Mendell; Samiah A Al-Zaidy; Louise R Rodino-Klapac; Kimberly Goodspeed; Steven J Gray; Christine N Kay; Sanford L Boye; Shannon E Boye; Lindsey A George; Stephanie Salabarria; Manuela Corti; Barry J Byrne; Jacques P Tremblay Journal: Mol Ther Date: 2020-12-10 Impact factor: 11.454