Adeno-associated virus (AAV) mediated gene therapy has emerged as a promising therapeutic for neuromuscular diseases; however, high systemic doses are required to achieve sufficient skeletal muscle and cardiac transduction. AAV-SLB101 was rationally designed as a vector with improved targeting capabilities to increase skeletal muscle and cardiac tropism through insertion of a peptide containing the RGD motif. This capsid is under first-in-human clinical evaluation in the Phase 1/2 INSPIRE DUCHENNE trial (NCT06138639 ) and the Phase 3 IMPACT DUCHENNE trial (NCT07160634) of SGT-003 of SGT-003, Solid Biosciences’ investigational, next-generation gene therapy for Duchenne muscular dystrophy (Duchenne). To better understand the pharmacokinetic and pharmacodynamic effects of this novel capsid in comparison to first-generation AAV capsids, a series of preclinical studies and early data from humans treated with SGT-003 were evaluated.
AAV-SLB101 demonstrated rapid transduction, increased muscle tropism and decreased liver uptake in both healthy animals and disease models (wild type and mdx mice, non-human primates, and human myotubes and iPSC-derived cardiac myocytes) when compared to first generation vectors (AAV9 and AAVrh74). In the mdx mouse model of disease, AAV-SLB101-mediated transgene expression was several-fold higher than AAVrh74 in multiple muscle groups and in the heart.
Early data from the INSPIRE DUCHENNE study demonstrates a similar pharmacokinetic and pharmacodynamic profile of rapid transduction, compelling expression and tolerability. Rapid clearance of the vector was seen in boys treated with SGT-003 while achieving high levels of transduction. We hypothesize that this rapid vector transduction may contribute to the encouraging safety and tolerability profile seen as of December 15, 2025, cutoff date, in the INSPIRE DUCHENNE trial. Further, SGT-003 has been administered with a short-term, corticosteroid-only prophylactic immunomodulatory regimen, signaling a limited inflammatory response to the vector. The translation of the pharmacokinetic and pharmacodynamic profile from preclinical models to interim human data suggest that the next-generation design of AAV-SLB101 may be a driving factor behind the robust biologic treatment effect and encouraging safety and tolerability profile observed in the INSPIRE DUCHENNE trial.