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Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

Authors :
K.D. Foust
Lyndsey Braun
Lindsay N. Alfano
Richard Shell
Thomas W. Prior
Sarah Corcoran
John T. Kissel
Samiah Al-Zaidy
Kathleen Church
Brian K. Kaspar
Linda Lowes
Sukumar Nagendran
Courtney Wells
Arthur H.M. Burghes
Douglas M. Sproule
W. Dave Arnold
Carlos Henrique Miranda
Kathrin Meyer
Louise R. Rodino-Klapac
Marjet D. Heitzer
James L’Italien
K. Berry
Allan Arman Kaspar
Jerry R. Mendell
Shibi Likhite
Jessica A. Cardenas
Source :
New England Journal of Medicine. 377:1713-1722
Publication Year :
2017
Publisher :
Massachusetts Medical Society, 2017.

Abstract

Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease.Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×10As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone.In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).

Details

ISSN :
15334406, 00284793, and 02122952
Volume :
377
Database :
OpenAIRE
Journal :
New England Journal of Medicine
Accession number :
edsair.doi.dedup.....af15cdce58cda254901625ceb6b14cab
Full Text :
https://doi.org/10.1056/nejmoa1706198