Expression of apparent full-length dystrophin in skeletal muscle in a first-in-human gene therapy trial using the scAAV9.U7-ACCA vector


Clinical Trials

Poster Number: 59


Megan Waldrop MD, Michael Lawlor , Tatyana Vetter , Emma Frair , Margaret Beatka , Hui Meng , Megan A. Iammarino DPT, Brenna Powers , Johan Harris , Maryann Kaler , Tabatha Simmons PhD, Nicolas Wein PhD, Kim McBride , Kevin Flanigan MD


1. Nationwide Children's Hospital, 4. Nationwide Children's Hospital, 7. Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, 8. Nationwide Children's Hospital, 11. Nationwide Children's Hospital, 12. Nationwide Children's Hospital, 14. Nationwide Children's Hospital

Exon duplications that cause Duchenne muscular dystrophy (DMD) are promising candidates for exon skipping therapies because skipping a single exon copy should result in wild-type transcript and full-length dystrophin expression. We developed a therapeutic exon skipping viral vector (scAAV9.U7-ACCA) comprising four copies of a modified U7snRNA containing antisense sequences targeting the splice donor (2 copies) and splice acceptor (2 copies) of the DMD exon 2, the most commonly duplicated exon. Following dose finding studies in Dup2 mice and after demonstrating lack of toxicity in non-human primates, we initiated a first-in-human clinical trial (NCT04240314). Here we present the planned 3-month post-infusion data in the first 2 subjects treated with 3.0×10^13 vg/kg. Both boys tolerated the treatment well, with only transient nausea and vomiting. No SAEs have been experienced to date and no biochemical measures of hepatic or other toxicity were seen. Muscle biopsy at 3 months shows expression of apparently full-length protein, quantified by Western blot at levels of >6% in the younger (9.0 yrs) subject and 1-2% in the older (13.7 yrs) subject, possibly reflecting differences in myofiber transfection due to differing degrees of dystrophic skeletal muscle changes. Consistent with dystrophin expression, serum CK decreased from 13,495 u/L to 560 u/L at 3 months post-injection in subject 1 and from 5,103 u/L to 947 u/L at 3 months in subject 2. Functional outcome measures remained stable or improved. These findings represent the first therapeutic expression of apparent full-length dystrophin in a human gene therapy trial and support continued clinical investigation.