Absence of Toxicity with Intravenous Dosing of the Exon 2-Skipping AAV9.U7-ACCA Vector in Non-Human Primates


Pre-Clinical Research

Poster Number: 5


Liubov Gushchina PhD, Emma Frair , Natalie Rohan , Adrienne Bradley , Tabatha Simmons PhD, Hemantkumar Chavan PhD, Hsin-Jung Chou PhD, Michelle Eggers , Megan Waldrop MD, Nicolas Wein PhD, Kevin Flanigan MD


1. Nationwide Children's Hospital, 2. Nationwide Children's Hospital, 3. Nationwide Children's Hospital, 4. Nationwide Children's Hospital, 5. Nationwide Children's Hospital, 6. Charles River Laboratories, 7. Audentes Therapeutics, 8. Audentes Therapeutics, 9. Nationwide Children's Hospital, 10. Nationwide Children's Hospital, 11. 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 AAV9 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 (3E13 vg/kg and 8E13 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.