Evaluation of early administration of AAV9-midlength-dystrophin in the mdx mouse model of Duchenne muscular dystrophy

Topic:

Pre-Clinical Research

Poster Number: 411 O

Author(s):

Gretchen Thomsen, PhD, Insmed Gene Therapy, Allan Kaspar, PhD, Insmed Gene Therapy LLC, San Diego, CA, USA, Lukas Bachmann, PhD, Insmed, Inc., Kathryn Hilde, PhD, Insmed, Inc., Laura Ferraiuolo, Insmed Gene Therapy LLC, San Diego, CA, USA, Binh Chu, PhD, Insmed, Inc., Maiya Lee, Insmed, Inc., Theresa Slaiwa, Insmed, Inc., Ryan Weiss, Insmed, Inc., Robert Cano, Insmed, Inc., Veronica J. Garcia, PhD, Insmed, Inc., Nuria Casanova, PhD, Insmed, Inc., Jaedyn Grin, Insmed, Inc., Melissa mcalonis-downes, UCSD, W. David Arnold, MD, University of Missouri - Columbia, Brian Kaspar, PhD, Insmed, Inc.

Background
Several hereditary diseases including Duchenne muscular dystrophy (DMD) are caused by recessive loss of function mutations in a single gene. In such cases, gene replacement therapy (gene therapy) is a promising strategy. Adeno-associated virus (AAV) is a preferred vector for gene therapy, but this strategy for treatment of DMD has faced the challenge of incompatibility of the large size DMD gene with limited packaging capacity of AAV.
Insmed is developing an AAV9-midlength-dystrophin construct (INSMid) that creates a 248 kilodalton (kDA) dystrophin for the treatment of DMD by utilizing a novel RNA end-joining (REJ) technology to piece together two RNA fragments within a cell to address traditional AAV capacity limits for gene therapies.
Objectives
Here, we evaluated the functional efficacy of INSMid following early intracerebroventricular (ICV) administration of doses ranging from 3.0E+10 to 3.1E+11 vector genomes (vg) in neonatal (p1) mdx mice. As INSMid uses a dual vector strategy, the dose is described per vector.
Results
Using the Aurora Scientific Whole Animal System for Mice, physiological measurements assessed contractile torque of plantar flexion muscles, including the gastrocnemius muscle. At ~115 days of age, INSMid-treated mdx mice exhibited substantial enhancements in peak plantar flexion twitch torque, with improvements of up to 96% at the high dose, compared with mdx-negative (–) controls. INSMid administration at this neonatal time point resulted in relative dose-dependent, significant improvements in plantar flexion peak torque at each dose when assessed at stimulation frequencies 80–160 Hz. Animals receiving the high dose of INSMid showed improvements of ≥125% relative to (–) controls over these frequencies and did not differ significantly from healthy WT controls.
Conclusions
This work supports further clinical studies to evaluate the possibility of improved dystrophin constructs that may have therapeutic benefit in muscles affected by the dystrophic pathology experienced in patients with DMD.