Real-World Study Suggests Motor Gains in SMA After Switching to Onasemnogene Abeparvovec From Nusinersen or Risdiplam Treatment

Children with spinal muscular atrophy (SMA) who transitioned from SMN2-targeted therapies—nusinersen or risdiplam—to the gene therapy onasemnogene abeparvovec demonstrated modest, but clinically meaningful improvements in motor function in a real-world observational study conducted at a single center in Poland.¹ Although most patients improved on standardized motor scales within 6 months of gene therapy infusion, the magnitude of gains was smaller than that reported in pivotal trials where onasemnogene abeparvovec was used as first-line therapy in infants.

The findings highlight the evolving treatment landscape for SMA, in which some patients receive sequential therapies due to treatment availability, reimbursement timing, or clinical decision-making. Investigators noted that prior exposure to SMN2-splicing modifiers did not appear to preclude motor improvement after gene therapy, although earlier treatment remains strongly associated with better outcomes.

The retrospective analysis included 40 children with genetically confirmed SMA treated at the Medical University of Lublin between April 2020 and March 2024. Before receiving onasemnogene abeparvovec, 38 patients had received nusinersen and 2 had received risdiplam.

The median interval between initiation of SMN2-modifying therapy and gene therapy was 13.5 months, with a wide range from 2 to 104 months. Notably, most patients were older and heavier than participants enrolled in pivotal gene therapy trials: 77.5% weighed more than 8.5 kg at the time of infusion, and only 25% were infants.

Patients discontinued prior therapy before receiving gene therapy. A washout period of 1 to 3 months was implemented for nusinersen, while no washout period was required for risdiplam. All patients received corticosteroid prophylaxis beginning one day before infusion to mitigate potential immune-mediated adverse effects.

Motor outcomes were assessed using either the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) or the Hammersmith Functional Motor Scale Expanded (HFMSE) depending on patient age and baseline function.

Investigators observed statistically significant improvements in motor function across the cohort within the first 6 months following gene therapy. Among patients evaluated using the HFMSE (n = 21), the median score increased from 30 at baseline to 36 at 6 months, corresponding to a median improvement of 7 points. In the CHOP-INTEND group (n = 19), the median score increased from 27 to 37, representing a median gain of 5 points (P = .0001).

Clinically meaningful improvement—defined as a ≥3-point increase in HFMSE or ≥4-point increase in CHOP-INTEND—was observed in 67.5% of patients at 1 month and 95% by 6 months.

A shift toward higher functional categories was also observed on both scales. On the CHOP-INTEND scale, 36.8% of patients achieved or maintained scores ≥40, a threshold rarely reached in untreated SMA populations.

Motor improvements were observed across most patient subgroups, including those stratified by SMA type, age at treatment, weight at infusion, and SMN2 copy number, although statistical comparisons were limited by small subgroup sizes.

Adverse events were consistent with the established safety profile of onasemnogene abeparvovec. All patients experienced transient symptoms—including weakness, fever, and vomiting—within several days of infusion.

Laboratory abnormalities were common. Elevated liver enzymes occurred in every patient, typically between days 5 and 7 after infusion, and were managed with corticosteroids. In several cases, steroid therapy was intensified or extended to control enzyme elevations.

Thrombocytopenia developed in 13 patients (32.5%), with nadir platelet counts occurring around days 5 to 6. Although, investigators reported no cases of thrombotic microangiopathy or multiorgan failure, which have been described as rare but serious complications of AAV-based gene therapy.²

SMA is an autosomal recessive neuromuscular disorder caused by deletions or mutations in the SMN1 gene, resulting in progressive degeneration of spinal motor neurons. Disease severity is influenced by the number of copies of the modifier gene SMN2, which produces limited amounts of functional SMN protein.³

Three disease-modifying therapies are currently available: nusinersen and risdiplam, which enhance SMN production by modifying SMN2 RNA splicing, and onasemnogene abeparvovec, which provides gene replacement through systemic delivery of a functional SMN1 gene using an AAV vector.⁴

The paper’s authors emphasized that earlier treatment remains a key determinant of therapeutic benefit in SMA. Although switching therapies can yield functional gains or stabilization, the magnitude of improvement may be constrained by disease progression. Prior exposure to nusinersen or risdiplam may help preserve motor neurons, potentially enabling patients to derive additional benefit from gene therapy even when administered later in childhood. Although, the relative benefit of switching compared with continuing SMN2-directed therapy remains uncertain.

The investigators also noted that gene therapy carries a distinct safety profile compared with splicing-modifying therapies, including risks of hepatotoxicity, immune reactions, and thrombotic microangiopathy. Older and heavier patients may have higher risks due to greater vector doses.²

The study’s retrospective design and single-center setting limit generalizability. The cohort was heterogeneous in age, disease severity, and treatment history, and subgroup analyses were constrained by small sample sizes.¹ Prospective trials, including studies evaluating therapy sequencing strategies, are ongoing and may provide clearer evidence regarding the role of switching to gene therapy after prior SMA treatment.

REFERENCES

1. Mikos M, et al. Real-world experience with switch to onasemnogene abeparvovec after initial therapy with nusinersen or risdiplam. Neuromuscular Disorders. Published 2025. https://doi.org/10.1016/j.nmd.2025.XXXX

2. Chand DH, Zaidman CM, Arya K, et al. Thrombotic microangiopathy following onasemnogene abeparvovec for spinal muscular atrophy. J Pediatr. 2021. https://pubmed.ncbi.nlm.nih.gov/33621612/

3. Prior TW. Spinal muscular atrophy diagnostics. J Child Neurol. 2010. https://pubmed.ncbi.nlm.nih.gov/20444815/

4. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017. https://www.nejm.org/doi/full/10.1056/NEJMoa1706198

5. Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy (STR1VE). Lancet Neurol. 2021. https://pubmed.ncbi.nlm.nih.gov/33743238/