mi405 AAV Gene Therapy in TIC-DUX4 mice Rescues Plantarflexor Torque

Topic:

Pre-Clinical Research

Poster Number: LB446

Author(s):

Robert Grange, PhD, Virginia Tec, Claire Yuan, MS, Department of Human Nutrition, Foods and Exercise and Metabolism Core at Virginia Tech Blacksburg, V, Lindsay Wallace, PhD, The Abigail Wexner Research Institute, Nationwide Children’s Hospital Columbus, OH., Amanda Sweeten, Department of Human Nutrition, Foods and Exercise and Metabolism Core at Virginia Tech Blacksburg, V, Jessica Camp, MS, The Abigail Wexner Research Institute, Nationwide Children’s Hospital Columbus, OH., Fang Ye, PhD, The Abigail Wexner Research Institute, Nationwide Children’s Hospital Columbus, OH., Gloria Zender, BA, The Abigail Wexner Research Institute, Nationwide Children’s Hospital Columbus, OH., Scott Harper, PhD, The Abigail Wexner Research Institute, Nationwide Children’s Hospital Columbus, OH.

The de-repression of the transcription factor Double Homeobox 4 (DUX4) gene induces progressive muscle weakness in facioscapulohumeral muscular dystrophy (FSHD). Gene silencing via RNA interference is a potential treatment to correct aberrant DUX4 expression. However, reliable outcome measures for testing therapeutic efficacy have proven challenging in both preclinical and clinical settings. Here we explore a preclinical physiological assay for muscle function as a potential outcome measure. We assessed hind limb muscle function in TIC-DUX4 mice, a model of FSHD. The study had two aims. In Aim 1, we established plantarflexor torque as a reliable differentiator of disease in TIC-DUX4 mice. We determined a tamoxifen dose of 15 mg/kg delivered via oral gavage once per week induced a significant decrease in plantarflexor torque in TIC-DUX4 FSHD mice compared to wild type mice. In Aim 2, mice aged 6-10-weeks were divided into two treatment groups. Each group received a single injection of mi405 AAV gene therapy at either a high dose (TIC-DUX4 -6E13, tamoxifen-induced) or a low dose (TIC-DUX4-3E13, tamoxifen-induced). Two other TIC-DUX4 groups, TIC-DUX4-saline (saline-injected, tamoxifen-induced) and TIC-DUX4-oil (uninjected, uninduced), served as controls. Additionally, iDUX mice (Cre negative, uninjected, administered with tamoxifen), were included as a third control group. Plantarflexor isometric torque was assessed weekly for five weeks (between 18-20 weeks of age) in all 5 groups, starting from baseline (uninduced) and continuing for four weeks post-tamoxifen induction. Both mi405-treated groups preserved isometric plantarflexor torque at 120 Hz, comparable to TICDUX4-oil controls. In contrast, TICDUX4-saline exhibited torque reduction from 2-4 weeks of tamoxifen induction (p<0.05). Our data demonstrated the therapeutic benefit of mi405 AAV gene therapy in TIC-DUX4 FSHD mice and established plantarflexor torque as a useful outcome measure in preclinical models of FSHD. (We gratefully acknowledge support from Solve FSHD).