Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study.

Autor: Nicolau S; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA., Malhotra J; Sarepta Therapeutics Inc., Cambridge, MA, USA., Kaler M; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA., Magistrado-Coxen P; Sarepta Therapeutics Inc., Cambridge, MA, USA., Iammarino MA; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA., Reash NF; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA., Frair EC; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA., Wijeratne S; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Kelly BJ; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., White P; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Lowes LP; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA., Waldrop MA; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; >Department of Neurology>, The Ohio State University, Columbus, OH, USA., Flanigan KM; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; >Department of Neurology>, The Ohio State University, Columbus, OH, USA.
Jazyk: angličtina
Zdroj: Journal of neuromuscular diseases [J Neuromuscul Dis] 2024; Vol. 11 (3), pp. 679-685.
DOI: 10.3233/JND-230107
Abstrakt: Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications.
Databáze: MEDLINE