NM_000344.4(SMN1):c.5C>G (p.Ala2Gly)

Onasemnogene abeparvovec (Zolgensma), an AAV9-based gene therapy delivering functional SMN1 cDNA, has transformed outcomes in spinal muscular atrophy type 1. A single intravenous infusion achieves broad motor neuron transduction via AAV9 CNS tropism, resulting in sustained SMN protein expression and dramatic improvement in survival and motor milestones compared to natural history.

The STR1VE trial (NCT03306277, completed) and preceding START trial demonstrated that single IV dosing (1.1 x 10^14 vg/kg) in presymptomatic or early-symptomatic SMA1 infants achieved event-free survival (alive without permanent ventilation) in over 90 percent of patients at 14 months, versus approximately 8 percent in historical controls. Italian registry 24-month follow-up data (PMID:41854353) confirmed durable motor gains. A JAMA Network Open comparative study (PMID:41060652) found onasemnogene comparable or superior to nusinersen for SMA1. The c.5C>G (p.Ala2Gly) variant (ClinVar VCV000009168) is classified as pathogenic and disrupts the N-terminal region critical for SMN self-oligomerization. FDA approved Zolgensma in May 2019 for SMA patients under 2 years of age.

AAV9 gene therapy carries hepatotoxicity risk — transient transaminase elevation is common, and rare cases of acute liver failure and thrombotic microangiopathy (TMA) have been reported in post-marketing surveillance. Pre-existing anti-AAV9 neutralizing antibodies (present in 5 to 15 percent of the population) preclude treatment. The c.5C>G variant specifically represents a compound heterozygous situation when paired with SMN1 deletion on the other allele; patients retaining partial SMN protein function may have somewhat different baseline severity. Re-dosing is not feasible due to anti-capsid humoral immunity after initial exposure. Long-term transgene expression durability beyond 5 to 7 years remains uncertain in growing children. Cost (approximately $2.1M) and IV delivery logistics limit access in resource-limited settings.

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.