Preclinical evaluation of INS1201 AAV9-micro-dystrophin via CSF administration as a potential therapy for Duchenne muscular dystrophy.

INS1201 is an investigational adeno-associated virus 9-micro-dystrophin gene transfer therapy under development as a potential treatment for Duchenne muscular dystrophy (DMD). Administered into the cerebrospinal fluid (CSF), this delivery approach efficiently targets skeletal and cardiac muscle. Here, we present preclinical findings that demonstrated improved muscle histopathology and functional efficacy in the mdx mouse model starting at 2.0E+11 vector genomes (vg)/mouse and safety in Good Laboratory Practice-compliant toxicology studies in mice and nonhuman primates (NHPs) following INS1201 treatment. INS1201 significantly reduced DMD-associated pathology, whereby increased muscle fiber size, improved overall histology, and decreased inflammation and fibrosis were observed in treated mdx mice compared with mdx control mice. Although wild-type levels were not observed in neuromuscular strength, sustained functional improvements confirmed INS1201's durable biological activity 1 year post-injection. Moreover, biodistribution and toxicology studies in mice and NHPs demonstrated effective transgene delivery to cardiac and skeletal muscles following INS1201 intra-CSF administration. Toxicology evaluations concluded that INS1201 was well tolerated at all tested doses, with the no observed adverse effect level set at the maximum feasible dose administered for both species (up to 8.0E+11 vg/mouse and 3.05E+14 vg/NHP). Collectively, these findings provided support for an INS1201 phase 1 human clinical study.