Clinician's Guide to Spinal Muscular Atrophy

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SMA and the Latest Disease-Modifying Therapies

Written by Margaret Anne Rockwood | Last updated July 7th, 2026
✅ Medically reviewed by Edward Smith, MD

 

The treatment landscape for spinal muscular atrophy (SMA) has undergone a remarkable transformation over the past decade. For many years, management consisted primarily of supportive care, including respiratory support, nutritional interventions, orthopedic management, and rehabilitation. Although these measures improved quality of life and survival, they did not address the underlying molecular defect.

Today, several disease-modifying therapies (DMTs) – such as nusinersen, onasemnogene abeparvovec-xioi, onasemnogene abeparvovec-brve, and risdiplam – can be prescribed to target the fundamental deficiency of survival motor neuron (SMN) protein and dramatically alter the disease’s natural course.

From Supportive Care to Molecular Therapy

Spinal muscular atrophy results from biallelic pathogenic variants in the SMN1 gene (mostly occurring from inherited defective SMN1 copies from both parents), leading to insufficient production of SMN protein and progressive motor neuron degeneration. The degree of protein production from the nearly identical SMN2 gene is the main determinant of SMA severity. This understanding provided the foundation for disease-modifying therapeutic development, where treatment either increases SMN protein production from SMN2 or replaces the missing SMN1 gene altogether.

Treatment is most effective when initiated early, ideally before symptoms develop. This observation has fueled universal newborn screening programs, which are now routine in all 50 states and gaining traction worldwide.               

FDA-Approved Disease-Modifying Therapies

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Therapy Mechanism of Action Route Target Patient Population
Nusinersen (Spinraza) Antisense oligonucleotide that modifies SMN2 splicing Intrathecal injections: initial loading series, then every 4 months Children and adults
Onasemnogene abeparvovec-xioi (Zolgensma) Gene replacement therapy delivering a functional SMN1 gene Single IV infusion Infants and young children (<2 years)
Onasemnogene abeparvovec-brve (Itvisma) Gene replacement therapy delivering a functional SMN1 gene Single intrathecal administration Children ≥2 years, adolescents, and adults with SMA and a confirmed SMN1 mutation
Risdiplam (Evrysdi) Small-molecule SMN2 splicing modifier Oral daily treatment Children and adults

ASOs

Nusinersen (Spinraza, Biogen) was the first US FDA-approved DMT for SMA in 2016. The antisense oligonucleotide (ASO) binds to the ISS-N1 regulatory sequence on SMN2 pre-mRNA before splicing occurs. By doing so, the drug displaces an hnRNP that is otherwise bound to the RNA and blocks/inhibits exon 7 inclusion. Exon 7 remains in the mature RNA, and more full-length SMN protein is produced. In addition, motor neurons receive more of the protein they need to survive.

In essence, rather than create a new gene or protein, the drug helps the existing SMN2 backup gene work better.

Before nusinersen, there was considerable skepticism about whether ASOs could reach enough neurons, persist long enough, and generate meaningful clinical effects. The success of nusinersen has largely answered those questions and helped to legitimize ASO therapies in other neurological conditions (eg, DMD, DM1, FSHD).

Unlike gene therapy, which changes the protein-production landscape for life, nusinersen’s effect on SM2 RNA processing attenuates with time as the drug is cleared from the body. This necessitates administration indefinitely, starting with 4 loading doses (Day 0, Day 14, Day 28, Day 63), followed by maintenance dosing every 4 months for life.

After injection into the cerebrospinal fluid (CSF), nusinersen enters motor neurons, binds SMN2 pre-mRNA, promotes exon 7 inclusion, and increases full-length SMN mRNA, thereby increasing SMN protein production.

Gene Replacement Therapies

Onasemnogene abeparvovec-xioi (Zolgensma, Novartis Gene Therapies) introduced a fundamentally different therapeutic approach to SMA when it was FDA-approved in 2019. Rather than modifying SMN2 RNA, this gene-replacement therapy uses an adeno-associated viral vector (AAV9) to deliver a functional, full-length copy of the SMN1 gene.

Administered as a one-time intravenous (IV) infusion, the therapy enables long-term production of SMN protein. Clinical trials have demonstrated substantial improvements in event-free survival, motor function, and achievement of developmental milestones.

The first use of onasemnogene abeparvovec-xioi in a pediatric patient was in 2014. That child was among a group of infants with SMA type 1 who participated in the pioneering clinical study conducted at Nationwide Children’s Hospital, in collaboration with Ohio State University Medical Center, involving 15 children <2 years of age. Follow-up studies of the 15 earliest treated children have demonstrated that a large majority have maintained substantial motor gains, with some achieving age-appropriate function. Those who benefited least had more severe disease and later treatment, underscoring the importance of early detection and intervention, presymptomatically when possible.

In 2025, the FDA approved onasemnogene abeparvovec-brve (Itvisma, Novartis Gene Therapies), an intrathecal formulation of the same gene replacement therapy. By delivering the vector directly into the cerebrospinal fluid, Itvisma expands treatment to children aged 2 years and older, while using a substantially lower vector dose than the intravenous formulation.

Both therapies address the underlying genetic defect by replacing the mutated SMN1 gene with a functional copy and are intended as one-time treatments.

Combination and Sequential Therapies

As clinical experience has expanded, clinicians have increasingly explored sequential and combination treatment strategies. Some patients transition from one therapy to another, while others receive gene therapy after prior treatment with nusinersen or risdiplam.

Although emerging evidence suggests that such approaches may be safe and beneficial in selected patients, ongoing studies may clarify questions of optimal sequencing, long-term outcomes and cost-effectiveness of these combinations.

SMN-C Splicing Modifiers

Approved in 2020, risdiplam (Evrysdi, Genentech) was the first FDA-indicated oral therapy for SMA. Like nusinersen, it increases functional SMN protein production by modifying SMN2 RNA splicing.

Clinical trials and retrospective studies have demonstrated that risdiplam improves or stabilizes motor function across a broad range of SMA types and ages. The convenience of daily oral administration has made it particularly attractive, especially for those who have difficulty with repeated intrathecal injections.

Current evidence suggests that risdiplam and nusinersen produce broadly comparable clinical outcomes, with no definitive head-to-head trial results to demonstrate clear superiority of one over the other. 

Looking Ahead

Despite extraordinary progress in disease-modifying therapies for SMA, challenges remain. Not all patients respond equally to treatment, and many continue to experience residual weakness, fatigue, orthopedic complications, and functional limitations. Future therapeutic strategies may combine SMN-restoring treatments with approaches aimed at muscle enhancement, neuroprotection, or motor neuron regeneration.

Nevertheless, the development of DMTs represents one of the most dramatic success stories in modern neuromuscular medicine. Within a single decade, SMA has evolved from a condition managed primarily through supportive care to one in which targeted molecular therapies can significantly alter disease trajectory, improve survival, and enhance quality of life.

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