Three FDA-Approved Therapies Have Transformed Spinal Muscular Atrophy, Yet Major Unmet Needs Remain

Spinal muscular atrophy (SMA) was once among the most feared diagnoses in pediatric neurology. Caused by the deletion of the SMN1 gene on chromosome 5, the disease triggers progressive degeneration of motor neurons in the anterior horn of the spinal cord, producing relentless muscle weakness, respiratory failure, and, in its most severe forms, death within the first two years of life. With an estimated incidence of roughly 10 per 100,000 live births, SMA remains the leading genetic cause of infant mortality worldwide. Yet a sweeping review published in Frontiers in Molecular Medicine by researchers at Clemson University argues that the past decade has rewritten that prognosis almost entirely, even as it cautions that the hardest work may still lie ahead.

The scientific foundation for this transformation was laid in 1995, when a landmark study identified SMN1 as the disease-causing gene. The authors found that SMN1 was deleted in 98.7 percent of patients in a 229-person cohort and mutated in the remainder. Crucially, humans carry a nearly identical backup copy called SMN2, which differs by a single base-pair transition from C to T in exon seven. That single nucleotide inactivates an exonic splicing enhancer and introduces an exonic splicing silencer, causing roughly 90 percent of the protein produced from SMN2 to be truncated and degraded by cellular machinery. Because SMA severity is inversely related to the number of SMN2 copies a patient carries, this backup gene became the central target for drug development.

Three FDA-approved disease-modifying therapies now anchor the treatment landscape. Nusinersen, marketed as Spinraza, is an antisense oligonucleotide that binds to a specific site within SMN2 pre-mRNA to promote inclusion of exon seven, restoring production of full-length SMN protein. Its development traced back to the discovery of an intronic splicing silencer called ISS-N1, and animal studies showed that blocking this element dramatically increased exon seven inclusion. The pivotal Phase 3 ENDEAR trial demonstrated significant improvement in infants with SMA Type 1, leading to accelerated FDA approval in 2016. Notably, in early 2026 the FDA approved a higher-dose regimen based on the DEVOTE study, with a safety profile consistent with more than a decade of clinical data.

Onasemnogene abeparvovec, known commercially as Zolgensma, takes a fundamentally different approach. It is a non-replicating adeno-associated virus serotype 9 vector that delivers a full-length SMN1 gene under the control of a hybrid promoter, capable of crossing the blood-brain barrier to reach spinal motor neurons after a single intravenous injection. A meta-analysis conducted four years after the drug’s release found mostly positive results, particularly in patients treated early in life, with motor milestone improvements that in many studies exceeded those achieved with nusinersen. A biodistribution study of post-mortem patient tissue confirmed vector genome presence throughout the central nervous system and in peripheral organs including skeletal muscle, heart, lung, and stomach.

Risdiplam, sold as Evrysdi, is the most recent addition and the first orally administered small-molecule SMN2 splicing modifier. The compound stabilizes the interaction between the 5-prime splice site on exon seven and the U1 small nuclear ribonucleoprotein, strengthening the splice site and reducing degradation. Unlike nusinersen, risdiplam crosses the blood-brain barrier because it does not bind to multi-drug resistant protein 1 and therefore cannot be pumped out of the central nervous system. A striking case study even documented prenatal therapy, with the drug administered orally to a mother carrying a confirmed SMA Type 1 fetus beginning at 32 weeks and 5 days of gestation; at 30 months of age, the child showed no manifestations of the disease. In a matching-adjusted indirect comparison, risdiplam-treated Type 1 patients showed a 78 percent reduction in mortality relative to historical nusinersen cohorts.

Despite these remarkable gains, the review emphasizes that the therapies are not curative. In 2024, approximately 75 percent of patients in the CureSMA database had received at least one disease-modifying therapy, yet only 47 percent of children and 19 percent of adults with SMA are ambulatory. Since the dawn of the therapy era, SMA mortality has dropped by nearly 80 percent, but 36 percent of patients still require some form of breathing support, and 89 percent of adults report that reaching new motor milestones remains their greatest unmet need. As patients live longer, a constellation of comorbidities has come into sharper focus, reshaping the clinical agenda.

Orthopedic complications illustrate this shift vividly. Between 60 and 90 percent of children with SMA develop scoliosis, which can complicate the intrathecal injections required for nusinersen and, if untreated, lead to chest deformities that further impair pulmonary function. Respiratory failure remains the leading cause of death, implicated in 72 percent of known SMA fatalities in a recent review. Gastrointestinal problems, including chronic constipation, dysphagia, and gastroesophageal reflux, are common, and eating difficulties can produce metabolic abnormalities such as glucose intolerance and insulin resistance. Cardiac irregularities, though less frequent, have been documented in infantile patients, ranging from congenital heart defects to cardiomyopathy.

The review also delves deeply into why motor neurons are selectively vulnerable to SMN deficiency, a question that remains only partially answered. SMN protein is best known for assembling small nuclear ribonucleoproteins, the complexes essential for recognizing splice sites and removing introns from pre-mRNA. Motor neurons harbor disproportionately high numbers of Cajal bodies, the nuclear structures where snRNP maturation is completed, likely reflecting their extraordinary demand for RNA metabolism to sustain constant electrical signaling. Low SMN reduces Cajal body numbers and, by extension, ribosome production. SMN also interacts with mRNA-binding proteins such as HuD, IMP1, and beta-actin that govern axonal transport and growth, and its deficiency disrupts neuromuscular junction maturation before symptoms even appear.

Looking forward, the authors survey a rich pipeline of alternative strategies. Induced pluripotent stem cells derived from patient skin fibroblasts have become powerful tools for drug screening and disease modeling, revealing pathways such as Fas ligand-mediated apoptosis and calcium dysregulation in cardiomyocytes. Gene editing approaches are particularly striking: a one-time base editing technique achieved an average of 87 percent permanent conversion of the disease-causing point mutation in mouse models with no detected off-target effects, while CRISPR-based prime editing of the ISS-N1 silencer sequence restored full-length SMN2 production in patient cells. Epidural spinal cord stimulation in a small cohort of adults produced a 40 percent increase in mean step length over four weeks, with benefits persisting even when the stimulator was switched off.

The review closes with a call for combination treatment strategies that build on existing therapies while addressing residual disease burden. Investigational agents such as apitegromab, a monoclonal antibody that blocks myostatin’s inhibition of skeletal muscle growth, are already being tested alongside approved drugs. The authors stress that SMA is fundamentally a multi-organ disease requiring multifactorial management, and that future research must ensure patients of all ages, including the growing population of adults living with the disease, are represented in treatment development. What began as a uniformly fatal diagnosis has become a chronic, manageable condition for many, but converting survival into truly restored function remains the defining challenge of the next decade.

Subject of Research: Disease-modifying therapies and future treatment directions for spinal muscular atrophy

Article Title: Spinal muscular atrophy in the disease-modifying therapy era: successes, limitations and future directions

Article References: Sexton, M. M., Crow, E. W., & Peng, C. A. (2026). Spinal muscular atrophy in the disease-modifying therapy era: successes, limitations and future directions. Frontiers in Molecular Medicine, 6, Article 1901311. https://doi.org/10.3389/fmmed.2026.1901311

Image Credits: AI Generated

DOI: 10.3389/fmmed.2026.1901311

Keywords: spinal muscular atrophy, SMN1, SMN2, nusinersen, onasemnogene abeparvovec, risdiplam, gene therapy, motor neurons, antisense oligonucleotide, comorbidities, base editing, iPSCs