Spinal Muscular Atrophy in the Disease-Modifying Therapy Era: Successes, Limitations and Future Directions

Major Points and Findings:

This paper reviews the approved drugs for SMA and does not report a stem cell study. It describes what nusinersen, risdiplam and onasemnogene abeparvovec have achieved, where each one falls short, and which problems remain now that children with SMA are living much longer. A short section covers cell-based approaches. All of the cell therapy work it cites for SMA was done in the laboratory or in animals, and none of it in patients.

The review is included here because it describes the needs that remain after treatment with the approved drugs. Since the disease-modifying drugs arrived, SMA mortality has fallen by nearly 80%. In the CureSMA database for 2024, about 75% of patients had received at least one of these drugs, yet only 47% of children and 19% of adults with SMA can walk. Thirty-six percent need some form of breathing support, and 89% of adults say that reaching new motor milestones is their greatest unmet need.

Aim:

To review the discovery and biology of SMA, explain why motor neurons are selectively vulnerable, summarise the clinical trials behind each approved therapy, and describe the alternative approaches under investigation, including cell-based ones.

Methods:

A narrative review from Clemson University, funded by the National Institutes of Health and Clemson Creative Inquiry, with no commercial relationships declared. The sections cover the history and classification of SMA, comorbidities, the biology of the SMN protein, the three approved therapies with trial tables, multidisciplinary care, and alternative targets. There was no systematic search, no pooled data and no formal quality appraisal, so the paper should be read as an overview.

Results:

The authors summarise the three approved therapies and their limitations in a table:

• Nusinersen (Spinraza) is an antisense oligonucleotide that corrects SMN2 splicing and is approved for all ages. It does not cross the blood-brain barrier, so it must be injected into the spinal canal every four months after the loading phase, which the authors note “may not work for all patients”, particularly those with scoliosis or who live far from a treatment centre. A higher-dose regimen from the DEVOTE study was approved by the FDA in early 2026.
• Onasemnogene abeparvovec (Zolgensma) is a one-time intravenous gene replacement using an AAV9 vector, which crosses the blood-brain barrier. It can only be given to children under two years old, which excludes all adults and any later-onset patient who was not picked up by screening. The authors describe it as showing the highest early motor gains and also the most adverse effects.
• Risdiplam (Evrysdi) is a daily oral splicing modifier for patients over two months. It has the fewest side effects, and 80% of patients in the cited analysis showed an increase in motor ability. Daily adherence is required and swallowing difficulties can complicate dosing.

As patients live longer, other problems become visible. Scoliosis affects 60% to 90% of children with SMA and can make the spine hard to reach for intrathecal injections. Respiratory failure remains the leading cause of death, implicated in 72% of deaths in one recent review. Gastrointestinal problems include chronic constipation, swallowing difficulty and reflux, and feeding difficulty can lead to glucose intolerance and insulin resistance. Cardiac abnormalities appear mainly in infants with types 1 and 2. In a case-control study, 71.4% of patients reported at least one comorbidity, and quality of life fell once there was more than one.

Cell therapy: The section on cell-based approaches is short.

• Induced pluripotent stem cells are described mainly as a research tool for modelling the disease and screening drugs. The transplantation successes cited are in SMARD1, a different and rarer condition, where neural stem cells derived from iPSCs engrafted in mouse spinal cord and improved neuromuscular junction function.
• The non-iPSC cell work is also in animals. Human amniotic stem cells injected into SMA mice before birth gave a 93.75% survival rate at birth with more myocytes and neurons. Neural stem cells transplanted into SMA mice migrated, differentiated into motor neurons and extended lifespan.
• The practical obstacle the authors identify is supply. Neural stem cells not derived from iPSCs are difficult to obtain and to expand in the numbers a transplant would need.

Other directions: Apitegromab, an antibody against myostatin, is being trialled as an add-on to the approved drugs. In the TOPAZ trial, patients with later-onset SMA gained a mean of 0.6 HFMSE points, with no hypersensitivity reactions. A trial combining risdiplam with an anti-myostatin antibody (MANATEE) is under way. Base editing and CRISPR approaches remain preclinical. In three adults, epidural electrical stimulation of the lumbosacral spinal cord for two hours a day over four weeks improved strength, increased mean step length by 40% and added 26 minutes to an endurance walking test, with effects persisting when the stimulator was switched off.

Conclusions:

The three approved drugs have greatly improved the outlook in SMA, but none is a cure and each only slows progression. SMA is a multi-organ disease and will probably need a multi-part treatment plan. The authors argue that further progress depends on combination strategies that build on the existing drugs and address the remaining problems. These include residual muscle weakness, breathing support needs, orthopaedic and gastrointestinal problems, and the needs of adults, who have the fewest options.

Background Information:

The SMN protein is made in every tissue, but it is expressed at higher levels in the spinal cord and it assembles the small nuclear ribonucleoproteins that splice messenger RNA. Motor neurons carry an unusually high number of Cajal bodies, the structures where that assembly finishes, which is one explanation for their vulnerability. SMN also transports messenger RNAs and proteins into the axon, so low SMN disturbs the growth and maintenance of the neuromuscular junction. Junction breakdown begins before symptoms appear, which is the biological argument for early treatment.

The review devotes a section to multidisciplinary care: physiotherapy and stretching, assistive seating and bracing, non-invasive ventilation and airway clearance, swallowing assessment and feeding support. It also notes that poor caregiver mental health predicted higher patient mortality in neurodegenerative disease, an argument for supporting families as well as patients.