Expression of apparent full-length dystrophin in skeletal muscle after administration of the scAAV9.U7-ACCA vector: 12 to 36 month follow up


Clinical Trials

Poster Number: 114


Megan Waldrop, MD, Nationwide Children's Hospital, Michael Lawlor, MD, PhD, Diverge Translation Science Laboratory, Tatyana Vetter, PhD, Nationwide Children's Hospital, Emma Frair, Nationwide Children's Hospital, Margaret Beatka, Diverge Translational Science Laboratory, Hui Meng, PhD, Diverge Translational Science Laboratory, Megan Iammarino, DPT, Nationwide Children's Hospital, Brenna Sabo, Nationwide Children's Hospital, Sharmada Subramanian, Nationwide Children's Hospital, Maryann Kaler, Nationwide Children's Hospital, Tabatha Simmons, PhD, Nationwide Children's Hospital, Kim McBride, MD, Nationwide Children's Hospital, Nicolas Wein, PhD, Nationwide Children's Hospital, Kevin Flanigan, MD, Nationwide Children's Hospital

Exon duplications in the DMD gene are promising exon skipping targets due to the potential for production of a full-length dystrophin product. We have previously shown the safety and early efficacy of the scAAV9.U7-ACCA vector delivered intravenously at a dose of 3.0 x 10^13 vg/kg in three participants with duplications of exon 2 in the DMD gene (9 years, 13.7 years and 7 months old at dosing). Here we report the continued safety through at least 12 months in all participants. Additionally, the early signs of efficacy have persisted. Serum CK reductions continue in all participants (ranging from 65% to 91% reduction from baseline values). Functional outcomes have improved in participant 1, slightly declined in participant 2, and all domains of development remain normal in participant 3. Muscle biopsy results showed dystrophin expression in all participants: ~7% in participant 1 at 12 months, ~1% in participant 2 at 12 months and ~70% at 8 months in participant 3 by western blot analysis. RT-PCR analysis showed exon skipping in all participants which was the most robust and persistent across timepoints in the youngest participant. Immunofluorescence also showed dystrophin expression in all participants with similar variability between participants. These data clearly show an age-at-dosing gradient of efficacy and support continued investigation, particularly in younger participants.