Low-dose AAV9-SMN1 with CNS-selective expression delivers efficacy and favorable safety in spinal muscular atrophy.

The approved AAV9-based gene therapy (onasemnogene abeparvovec) extends survival and motor milestones in spinal muscular atrophy (SMA) type 1 but is administered at a high dose (1.1E14 vg/kg) and carries a boxed warning for liver injury. We engineered SKG0201, a self-complementary AAV9 vector encoding codon-optimized SMN1 under central nervous system (CNS)-selective regulatory cassette (Syn-Cbin-rGBpA), driving CNS-preferential transgene expression and minimizing acute peripheral overexpression. In SMNΔ7 mice with a median survival of 15 days, a single 1E11 vg/pup (equivalent to 6.67E13 vg/kg) injection of SKG0201 extended median survival beyond 160 days, normalized rotarod and grip performance, and ameliorated neuropathology. No aminotransferase elevations were elicited up to 4E11 vg/pup. In a phase I trial (NCT06191354), 10 symptomatic infants with SMA type 1 received 3.7-5.5E13 vg/kg SKG0201. This interim analysis reports safety and preliminary efficacy data with at least 24 weeks of follow-up. At 24 weeks post treatment, 80% remained free from permanent ventilation, 6 of 8 survivors (75%) achieved a≥4-point increase in CHOP INTEND score, and 4 of 8 survivors (50%) achieved head control. Treatment-related adverse events were largely transient and manageable, with no high-grade drug-related hepatotoxicity observed. SKG0201's design reduces the viral dose requirement while optimizing CNS target engagement, suggesting an improved therapeutic index for SMA gene therapy.