Introduction: Duchenne muscular dystrophy is caused by loss of dystrophin, resulting in destabilization of the dystrophin-associated protein complex (DAPC). Disruption of the DAPC weakens sarcolemmal integrity, leading to membrane fragility, chronic myofiber damage, and persistent activation of degeneration–regeneration cycles. Attempted muscle regeneration from satellite cells as a consequence of an ongoing muscle injury process results in a high level of embryonic myosin heavy chain (eMHC) in muscle fibers in Duchenne. Thus, restoring expression and localization of the entire protein complex, especially the sarcoglycans, is a critical therapeutic goal for re-establishing DAPC function and preventing severe muscle disease in Duchenne which can be characterized by a reduction in eMHC.
Objectives: To evaluate whether SGT-003, Solid’s next-generation AAV microdystrophin gene therapy, restores DAPC stability, improves sarcolemmal integrity, and normalizes the degeneration–regeneration process.
Methods: Sarcolemmal localization of β-Sarcoglycan and related DAPC components was assessed in muscle biopsies pre- and post-SGT-003 administration. Serum creatine kinase (CK) and titin fragments were quantified as biomarkers of sarcolemmal damage. eMHC expression was measured as a marker of active degeneration–regeneration.
Results: Following SGT-003 treatment, β-Sarcoglycan and additional sarcoglycans showed increased sarcolemmal staining, consistent with reconstitution of the DAPC. Serum CK and titin levels decreased from baseline, supporting improved sarcolemmal integrity. Concomitantly, eMHC-positive fibers were reduced, indicating a reduction in ongoing myofiber necrosis and regeneration cycles.
Conclusions: SGT-003 produces compelling biological evidence of DAPC restoration, enhanced sarcolemmal resilience, and a measurable reduction in ongoing muscle injury. Critically, the decline in eMHC suggests that muscle fibers are no longer trapped in a perpetual injury-repair loop—a shift that may enable true structural preservation and improved long-term function for patients with Duchenne. These findings underscore the therapeutic importance of restoring sarcoglycans as integral DAPC components and support the potential of SGT-003 to meaningfully alter disease trajectory.