INS1201 is an AAV9-micro-dystrophin construct being evaluated for the potential treatment of Duchenne muscular dystrophy (DMD). INS1201 expresses a segment of the dystrophin protein that demonstrates efficacy in the mdx mouse and is delivered via a single intrathecal (IT) administration.
The nonclinical program for INS1201 comprises: proof of concept intrathecal route of administration and AAV9 biodistribution in mice and nonhuman primates (NHPs), histopathological and functional strength and electrophysiology efficacy in the mdx model, a GLP toxicology study in wild-type (WT) mice and a GLP toxicology study in NHPs.
Nonclinical histopathological and functional efficacy studies with INS1201 demonstrated qualitative improvement in general muscle histology, increased fiber size, decreased inflammation and fibrosis, and quantitative improvement in muscle strength and physiology compared to control mdx animals. Dose ranging studies were conducted in mdx mice to determine a minimally efficacious dose as well as a dose that nearly corrected the diseased muscle phenotype relative to control mdx mice. These studies provide strong evidence to support further clinical studies of INS1201 to evaluate therapeutic benefit in DMD. Treatment of mdx mice, a commonly used mouse model of DMD, with INS1201 resulted in: 1) broadly transduced muscle tissues as analyzed via droplet digital polymerase chain reaction (ddPCR), as well as immunohistochemistry and protein analysis of micro-dystrophin, 2) reduced DMD disease pathology as assessed by histopathological analyses, 3) improved forelimb and hindlimb strength and physiology indicating that INS1201 has biological activity and functional activity in a mouse model.
Biodistribution studies in both mice and NHPs demonstrated significant vector genome delivery to muscle groups throughout the body by delivery to the cerebrospinal fluid (CSF), as well as effective cardiac muscle targeting with limited distribution to the liver compared to systemic dosing.
GLP toxicology studies were performed in WT mice and NHP. The overall in-life health parameters, clinical pathology, and necropsy results from each 3-month study indicate INS1201 was well tolerated at all doses administered in each species. The apparent no observed adverse effect level (NOAEL) for INS1201 administered intracerebroventricularly in mice and intrathecally in NHP was the maximal dose administered in each respective study.