direct-reprogramming-human-fibroblasts-into-myoblasts-to-investigate

Direct Reprogramming of Human Fibroblasts into Myoblasts to Investigate Therapies for Neuromuscular Disorders

Investigations into both the pathophysiology and therapeutic targets in muscular dystrophies have been hampered by the limited proliferative capacity of ...

The Research Institute at Nationwide Children’s Hospital

Therapeutic exon skipping as a treatment for Duchenne muscular dystrophy (DMD) has largely concentrated on delivery of antisense oligomers to treat out-of-frame exon deletions. Here we report on the preclinical development of an AAV-encapsidated viral vector containing four copies of the non-coding U7 small nuclear RNA (U7snRNA), each targeted to either the splice donor or the splice acceptor sites of DMD exon 2. We have previously shown that delivery of this vector (rAAV9.U7.ACCA) to the Dup2 mouse model results in expression of full-length dystrophin from wild-type DMD mRNA, as well as an IRES-driven isoform translated only in the absence of exon 2 (Del2 mRNA). Here we present the data from a rigorous dose-escalation toxicity study in nonhuman primates, encompassing two doses (3 x 1013 vg/kg and 8 x 1013 vg/kg) and two time points (3- and 6- months post-injection). No evidence for significant toxicity was seen by biochemical, histopathologic, or clinical measures, providing evidence for safety that led to initiation of a first-in-human clinical trial.

Emma C. Frair

Center for Gene Therapy

The Research Institute at Nationwide Children’s Hospital

Direct Reprogramming of Human Fibroblasts into Myoblasts to Investigate Therapies for Neuromuscular Disorders

Emma C. Frair

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The Research Institute at Nationwide Children’s Hospital

Direct Reprogramming of Human Fibroblasts into Myoblasts to Investigate Therapies for Neuromuscular Disorders

Center for Gene Therapy