A single infusion of a gene therapy delivered within the first months of life continues to transform the course of one of the most devastating neuromuscular diseases of infancy, according to a comprehensive two-year analysis of real-world outcomes drawn from the Italian national registry. The new findings, published in Annals of Clinical and Translational Neurology, track 64 children with type I spinal muscular atrophy (SMA) who received onasemnogene abeparvovec, an adeno-associated viral vector-based treatment designed to correct the underlying genetic defect in a single intravenous dose. The results show that motor improvement does not stop at the one-year mark, as most clinical trials initially reported. Instead, children continue to gain strength and motor milestones throughout the second year after treatment, with more than 80 percent of children who could not sit at the time of therapy going on to achieve independent sitting — a milestone that, by the natural definition of their disease, would have been impossible without intervention.
Spinal muscular atrophy is caused by mutations in the SMN1 gene, which deprives spinal motor neurons of functional survival motor neuron (SMN) protein. The resulting degeneration produces progressive weakness of skeletal muscles and, in the most severe form, compromises breathing and swallowing. Before disease-modifying therapies existed, children with SMA type I — defined by symptom onset within the first six months of life and an inability to sit unsupported — almost invariably died or required permanent mechanical ventilation by 20 months of age. The introduction of onasemnogene abeparvovec, which delivers a functional copy of SMN1 directly to motor neurons via an AAV9 vector, fundamentally changed this trajectory. In pivotal trials such as STR1VE and SMART, which enrolled carefully selected infants under six months without bulbar or respiratory complications, survival rates climbed to between 90 and 100 percent and most infants gained the ability to sit.
Real-world experience, however, has always been more complicated. Once the therapy became commercially available, its approved label expanded well beyond the narrow trial population, allowing treatment of older and heavier infants, children with bulbar and respiratory impairment, and patients who had already been exposed to other disease-modifying therapies such as nusinersen or risdiplam. These broader cohorts have shown greater variability in outcome: while survival and motor gains remain the norm, not every child achieves independent sitting within the first year, and older, heavier children tend to respond less robustly. Recognizing that some milestones may simply take longer to emerge, the Italian research consortium set out to determine whether extended follow-up would reveal continued functional progress that shorter studies had missed.
The new analysis draws on the Italian SMA Consortium (ITASMAC) registry and includes all consecutive symptomatic type I patients treated with onasemnogene abeparvovec who completed at least 24 months of follow-up, regardless of SMN2 copy number, age or weight at treatment, prior therapy, or sex. The cohort of 64 children was divided into three groups based on treatment history: 27 received the gene therapy as monotherapy, 9 received a short bridging course of nusinersen or risdiplam for less than three months before switching, and 28 had been treated with another disease-modifying drug for a median of nearly two years before transitioning to the gene therapy. Motor function was assessed with the validated CHOP-INTEND scale, and milestone acquisition, nutritional status, and respiratory support were documented prospectively at each clinical visit across the two-year observation window.
The baseline characteristics of the three treatment groups differed markedly, reflecting the realities of sequential therapy in clinical practice. Children treated with the gene therapy alone were the youngest, with a mean age at infusion of just 0.33 years, while those who switched from prior therapy were significantly older at a mean of 2.92 years. Switch patients also entered with the highest baseline CHOP-INTEND scores — a mean of 47.8 compared with 30.6 among monotherapy patients — because their earlier treatment had already partially stabilized their motor function. To disentangle these overlapping variables, the researchers built two separate multivariable linear mixed-effects models, one anchored to pretreatment status and one to chronological age at infusion, both adjusting for baseline motor score and SMN2 copy number.
Across the entire cohort, motor scores improved dramatically, rising on average by roughly 20 CHOP-INTEND points per year of follow-up. Yet the pace of improvement was not uniform. Children who switched to the gene therapy after prolonged prior treatment improved significantly more slowly than those treated without prior exposure, a difference that persisted even after accounting for their higher starting scores. Similarly, in the age model, each additional month of age at infusion was associated with a measurable slowing of the rate of motor gain. The researchers caution that age and pretreatment status are so strongly intertwined in this observational dataset that the independent contribution of each factor cannot be definitively separated — older children were, almost by definition, the ones who had spent more time on prior therapies. Both patterns may simply reflect that children who received early prior treatment had already captured much of their achievable therapeutic benefit before the gene therapy was administered.
The milestone data paint a striking picture of how timing shapes outcome. Of the 49 children who could not sit at the time of infusion, 40 — or 80 percent — achieved independent sitting during the two years of follow-up, and 5 achieved independent walking. Crucially, 12.5 percent of those who gained sitting did so only after the 18-month mark, well beyond the window captured by earlier trials, confirming that meaningful motor gains continue into the second year and that premature judgments about treatment failure may be unwarranted. Every child treated before six months of age who carried three copies of the SMN2 modifier gene achieved sitting within the age-appropriate physiological window. In contrast, among infants with two SMN2 copies, outcomes ranged from on-time sitting to never achieving the milestone, with low baseline CHOP-INTEND scores and the presence of bulbar or respiratory impairment most consistently associated with less favorable trajectories, though not invariably so for every individual child.
Bulbar and respiratory function also evolved favorably for many children. Of the 54 children fed orally at the time of treatment, only 3 required a feeding tube during follow-up, while 2 of the 10 who already had tubes successfully transitioned back to oral feeding. On the respiratory front, none of the 43 children already requiring ventilatory support at baseline progressed to tracheostomy, and 3 were ultimately weaned off ventilation altogether. Among infants who entered treatment with no evident respiratory or bulbar impairment, fewer than 5 percent needed a gastrostomy and only 12 percent required non-invasive ventilation over the two-year period. Safety surveillance throughout the second year after treatment identified no adverse events, and the authors note that no new safety signal emerged between the first and second years, consistent with prior international reports.
Set against the natural history of the disease, the results are transformative. Untreated children with SMA type I never achieve independent sitting, and more than 90 percent die or require permanent ventilation by age two. In this cohort, fewer than 20 percent of the children who could not sit at treatment failed to gain that milestone within two years. The authors acknowledge the interpretive limits of their observational design — confounding by indication, selection bias, and the entanglement of age with treatment history all complicate attribution, and larger cohorts with methods such as propensity score matching would be needed to fully resolve them. Even so, the findings carry a clear clinical message: two years after a single infusion, children with the most severe form of spinal muscular atrophy continue to gain function, milestones once considered unattainable are achieved, and the duration of follow-up matters when judging the true efficacy of this therapy. Future studies, the researchers suggest, should extend to cognitive, behavioral, and language outcomes to fully characterize the long-term neurodevelopmental trajectory of these gene therapy-treated children.
Subject of Research: Long-term efficacy of onasemnogene abeparvovec gene therapy in type I spinal muscular atrophy
Article Title: Onasemnogene Abeparvovec in Type I Spinal Muscular Atrophy: 24‐Month Follow‐Up From the Italian Registry
Article References: Pane, M., Coratti, G., Cutrì, C., Varone, A., Masson, R., D’Amico, A., Sansone, V., Messina, S., Ricci, F., Ticci, C., Bruno, C., Agosto, C., Benedetti, F., Pini, A., Siliquini, S., Filosto, M., Zambon, A., Bitetti, I., Manna, M. R., … the ITASMAC working group (2026). Onasemnogene Abeparvovec in Type I Spinal Muscular Atrophy: 24‐Month Follow‐Up From the Italian Registry. Annals of Clinical and Translational Neurology, 13(9), 1866-1877. https://doi.org/10.1002/acn3.70356
Image Credits: AI Generated
DOI: 10.1002/acn3.70356
Keywords: spinal muscular atrophy, gene therapy, onasemnogene abeparvovec, SMN1, AAV9 vector, CHOP-INTEND, motor milestones, Italian registry, nusinersen, risdiplam, real-world data, pediatric neurology
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Juliet Wilcox. (September 11, 2026). Gene Therapy Shows Lasting Two-Year Gains in Infants With Severe Spinal Muscular Atrophy. Scienmag. https://scienmag.com/gene-therapy-shows-lasting-two-year-gains-in-infants-with-severe-spinal-muscular-atrophy/
Juliet Wilcox. “Gene Therapy Shows Lasting Two-Year Gains in Infants With Severe Spinal Muscular Atrophy.” Scienmag, 11 September 2026, https://scienmag.com/gene-therapy-shows-lasting-two-year-gains-in-infants-with-severe-spinal-muscular-atrophy/. Accessed 11 September 2026.
Juliet Wilcox. “Gene Therapy Shows Lasting Two-Year Gains in Infants With Severe Spinal Muscular Atrophy.” Scienmag. September 11, 2026. https://scienmag.com/gene-therapy-shows-lasting-two-year-gains-in-infants-with-severe-spinal-muscular-atrophy/
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Tags: AAV9 vectorCHOP-INTENDearly treatment for infant spinal muscular atrophygene therapygene therapy for spinal muscular atrophygenetic correction for SMA using viral vectorsimpact of gene therapy on SMA disease progressionItalian registrylong-term effects of SMA gene therapymotor milestone improvement in SMA infantsmotor milestonesneurological improvements in SMA patientsnusinersenonasemnogene abeparvoveconasemnogene abeparvovec clinical outcomespediatric neurologyreal-world datareal-world SMA treatment datarisdiplamsevere infant spinal muscular atrophy treatmentSMN1SMN1 gene mutation therapyspinal muscular atrophytwo-year follow-up on SMA gene therapy
