Treatment of DMD 5’ Mutations through Two Different Exon 2 Skipping Strategies: rAAV9.U7snRNA Mediated Skipping and Antisense Morpholino Oligomers
Year: 2016
Type: article
Abstract: Duchenne muscular dystrophy (DMD) is an X-linked progressive disease characterized by loss of dystrophin protein as a result of truncating mutations in the DMD gene.Initial exon-skipping therapies have sought to treat deletion mutations that abolish an open reading frame (ORF) because when skipped, an ORF can be restored and produce an internally deleted, yet partially functional protein.In contrast, skipping of one copy of a duplicated exon would be expected to result in a full-length transcript and production of a wild type protein.To test this approach, we have developed a mouse model which contains a duplication of exon 2 (Dup2), the most common single exon duplication in patients.We are developing exon-skipping therapies for duplication mutations, which account for around 6%-11% of all duplication mutations by testing both virally (AAV) mediated skipping induced by a modified U7snRNA (rAAV9.U7.ACCA) and antisense oligomer-induced skipping in the Dup2 mouse.Dose escalation studies of both intramuscular and systemic delivery of scAAV9.U7.ACCA show efficient skipping of exon 2, along with increased expression of properly localized dystrophin that restores muscle function.Furthermore, intramuscular injections of antisense oligomers results in widespread skipping and properly localized dystrophin protein.These data suggest that
Author: Tabatha R. Simmons
Institution: The Ohio State University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2610164482