Intrathecal onasemnogene abeparvovec expands treatment window for SMN1 c.5C>G carriers

Recent phase 3 trials of intrathecal onasemnogene abeparvovec (Zolgensma) demonstrate that AAV9-mediated SMN1 gene replacement can be effective in both treatment-naive and treatment-experienced SMA patients, including those with missense variants like c.5C>G (p.Ala2Gly). Intrathecal delivery bypasses the dose-limiting hepatotoxicity seen with intravenous administration and may enable treatment of older and heavier patients previously ineligible for IV Zolgensma.

Two pivotal phase 3 trials published in Nature Medicine (2026) evaluated intrathecal onasemnogene abeparvovec. Proud et al. (PMID: 41360993) reported results in treatment-naive patients, while Kwon et al. (PMID: 41360995) studied treatment-experienced patients who had previously received nusinersen or risdiplam. Both trials demonstrated motor milestone achievements beyond natural history expectations. The SMART phase 3b study (McMillan et al., Neurology 2025; PMID: 39804575) further confirmed the safety and efficacy profile of IV onasemnogene abeparvovec in a broader pediatric SMA population. A phase IV trial (Proud et al., J Clin Invest 2025; PMID: 40956616) evaluating sequential nusinersen after onasemnogene abeparvovec suggested potential benefits of combination approaches. For the c.5C>G (p.Ala2Gly) variant specifically, this pathogenic missense mutation disrupts SMN protein stability, making full-length SMN1 transgene delivery via AAV9 a mechanistically appropriate strategy since it provides a functional copy of the gene regardless of the specific point mutation.

Long-term durability of transgene expression beyond 5 years remains uncertain. Pre-existing anti-AAV9 antibodies can preclude treatment in a subset of patients (estimated 5-10% depending on population). The intrathecal route, while avoiding systemic hepatotoxicity, carries procedural risks including post-lumbar puncture headache. Variant-specific response data for c.5C>G are limited given the rarity of individual point mutations in SMA (most cases involve exon 7 deletions). Cost and global access remain significant barriers, with the therapy priced above $2 million per treatment.