Authors: Ryan Wuebbles, David Craig, Macie Mackey, Haley Russell, Connor Hendrie, Jay Griffin, Sonja Gordon, Hailey Hermann, Marisela Dagda, Peter Nghiem, Dean Burkin
Affiliations: Sarcomatrix Corporation; Strykagen Corporation; University of Nevada-Reno; Texas A&M University
Introduction: Duchenne Muscular Dystrophy (DMD) is a fatal X-linked muscle-wasting disease caused by mutations in the dystrophin gene. The α7β1 integrin is the primary laminin-binding protein in skeletal and cardiac muscle and serves in an overlapping capacity to the dystrophin-glycoprotein complex. Enhancing α7β1 integrin levels has been validated as a mutation-independent strategy to stabilize the sarcolemma and compensate for dystrophin loss.
Objective: To evaluate the efficacy, safety, and pharmacokinetic profile of S969, a lead oral small molecule designed to enhance endogenous α7β1 integrin expression.
Methods: S969 was identified through a high-throughput screen of over 400,000 compounds. Efficacy was assessed in the mdx mouse and the Golden Retriever Muscular Dystrophy (GRMD) canine models. Primary endpoints included ex vivo and in vivo muscle force, physical activity, serum biomarkers, and cardiac function. Safety and pharmacokinetics were also evaluated in non-human primates.
Results: S969 targets a key kinase to upregulate α7β1. In short-term mdx studies, S969 improved total distance traveled (approximately 12,000–14,000 cm vs. 8,000–10,000 cm vehicle) and vertical activity. Long-term (49-week) treatment increased specific tetanus force in the EDL to ~225 kN/m² compared to ~175 kN/m² in vehicle controls. In aged mdx mice (11–20 months), S969 maintained a 100% survival rate and preserved ejection fraction (~55% vs. ~42% vehicle). In the GRMD model, S969 treatment significantly blunted exercise-induced creatine kinase (CK) spikes (2,000–15,000 U/L vs. 30,000–85,000 U/L vehicle) and increased MRI-measured muscle cross-sectional area by 0.15–0.20 cm².
Conclusions: S969 is a potent, oral α7β1 integrin enhancer that improves skeletal and cardiac muscle function across multiple species. The molecule is safe and well-tolerated in mice, canines, and primates. These results support the continued advancement of S969.