Wein et al. 2022 (PRJNA800783)

General Details

Title Systemic Delivery of an AAV9 Exon Skipping Vector Significantly Improves or Prevents Features of Duchenne Muscular Dystrophy in the Dup2 Mouse Model
Organism
Number of Samples 2
Release Date 2022/01/26 00:00
Sequencing Types
Protocol Details

Study Links

Repository Details

SRA SRP356873
ENA SRP356873
GEO
BioProject PRJNA800783

Publication

Title
Authors Wein N,Vetter TA,Vulin A,Simmons TR,Frair EC,Bradley AJ,Gushchina LV,Almeida CF,Huang N,Lesman D,Rajakumar D,Weiss RB,Flanigan KM
Journal Molecular therapy. Methods & clinical development
Publication Date 2022 Sep 8
Abstract Duchenne muscular dystrophy (DMD) is typically caused by mutations that disrupt the DMD reading frame, but nonsense mutations in the 5' part of the gene induce utilization of an internal ribosomal entry site (IRES) in exon 5, driving expression of a highly functional N-truncated dystrophin. We have developed an AAV9 vector expressing U7 small nuclear RNAs targeting DMD exon 2 and have tested it in a mouse containing a duplication of exon 2, in which skipping of both exon 2 copies induces IRES-driven expression, and skipping of one copy leads to wild-type dystrophin expression. One-time intravascular injection either at postnatal days 0-1 or at 2 months results in efficient exon skipping and dystrophin expression, and significant protection from functional and pathologic deficits. Immunofluorescence quantification showed 33%-53% average dystrophin intensity and 55%-79% average dystrophin-positive fibers in mice treated in adulthood, with partial amelioration of DMD pathology and correction of DMD-associated alterations in gene expression. In mice treated neonatally, dystrophin immunofluorescence reached 49%-85% of normal intensity and 76%-99% dystrophin-positive fibers, with near-complete correction of dystrophic pathology, and these beneficial effects persisted for at least 6 months. Our results demonstrate the robustness, durability, and safety of exon 2 skipping using scAAV9.U7snRNA.ACCA, supporting its clinical use. © 2022 The Authors.
PMC PMC9356240
PMID 35949298
DOI
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)
SRR17769725 PRJNA800783 Mus musculus Ribo-Seq
SRR17769724 PRJNA800783 Mus musculus Ribo-Seq
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)

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