How is spinal muscle atrophy (SMA) treated?

Updated: Aug 11, 2020
  • Author: Ashish S Ranade, MBBS, MS, MRCS; Chief Editor: Jeffrey A Goldstein, MD  more...
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Curative therapy for SMA has been elusive. The survival rate is poor among young patients. Interest has arisen in the use of inhibitors of gamma-aminobutyric acid (GABA) synthesis, with promising results. Developments in the use of antisense-based therapy have been described. [34, 35, 36, 37, 38]

Research into genetic therapies, as well as molecular and stem cell–mediated therapies, is ongoing. [39, 40, 41]  The Cure SMA drug pipeline has identified four possible treatment targets [42] :

  • Replacement or correction of the faulty  SMN1
  • Modulation of the low-functioning  SMN2 (the “backup gene”)
  • Neuroprotection of the motor neurons affected by loss of SMN protein
  • Muscle protection to prevent or restore the loss of muscle function in SMA

Pharmacologic therapy


In December 2016, the US Food and Drug Administration (FDA) approved nusinersen, the first drug approved for treatment of children (including newborns) and adults with SMA. Nusinersen is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron (SMN) protein deficiency. Through in-vitro assays and studies in transgenic animal models of SMA, nusinersen was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein. [43]

FDA approval was based on the ENDEAR trial, a phase 3 randomized, double-blind, sham-controlled study (N = 121) in patients with infantile-onset (most likely to develop type I) SMA. [44]  At a planned interim analysis, the rate of achieving a motor milestone response was higher in infants treated with nusinersen (40%) than in those not so treated (0%), as measured by the Hammersmith Infant Neurological Examination (HINE). Additionally, a smaller percentage of patients died in the nusinersen group (23%) than in the untreated group (43%).

Interim findings from CHERISH, another phase 3 trial, involved 126 nonambulatory patients with later-onset SMA (consistent with type II), including those with the onset of signs and symptoms at 6 months or later and an age of 2-12 years at screening. [45]  Prespecified interim analysis demonstrated a difference of 5.9 points at 15 months between the treatment arm (n = 84) and the sham-controlled arm (n = 42), as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE). From baseline to 15 months of treatment, patients in the nusinersen group achieved a mean improvement of 4.0 points in the HFMSE, whereas those in the control group showed a mean decline of 1.9 points.

A 2020 Cochrane review reported, on the basis of moderate-certainty evidence, that nusinersen improves motor function in type II SMA. [46]  Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid, and the combination of valproic acid and acetyl-L-carnitine probably have no clinically important effect on motor function in SMA types II or III (or both), on the basis of low-certainty evidence. Olesoxime and somatropin may also have little to no clinically important effect, but the evidence was of very low certainty.

A 2019 Cochrane review reported, on the basis of very limited evidence, that intrathecal nusinersen probably prolongs ventilation-free and overall survival in infants with type I SMA. [47]  It is also probable that a greater proportion of infants treated with nusinersen versus a sham procedure achieve motor milestones and can be classed as responders to treatment on clinical assessments (HINE-2 and Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND]). The proportion of children experiencing adverse events and serious adverse events is no higher with nusinersen than with a sham procedure (moderate-certainty evidence). It is uncertain whether riluzole has any effect in type I SMA.

A multicenter observational study reported that there is some evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q SMA, with clinically meaningful improvements noted in motor function. [48]

The American Academy of Neurology (AAN) stated that evidence of efficacy is currently greatest for treatment of infantile- and childhood-onset SMA in the early and middle symptomatic phases. Whereas approved indications for nusinersen use in North America and Europe are broad, payer coverage for populations outside those in clinical trials remain variable. Evidence, availability, cost, and patient preferences all influence decision-making regarding nusinersen use. [49]

Onasemnogene abeparvovec

Onasemnogene abeparvovec, approved by the FDA in May 2019, is a recombinant adenoassociated virus serotype 9 (AAV9)-based gene therapy designed to deliver a copy of the gene encoding the SMN protein. It is indicated for gene replacement therapy in children aged 2 years or younger with type I SMA (also called Werdnig-Hoffman disease) who have biallelic mutation in SMN1.

Approval was based on the ongoing phase 3 STR1VE trial [50]  and the completed phase 1 START trial. [51]  In the START trial, patients with type I SMA received a single dose of intravenous (IV) AAV9 carrying SMN complementary DNA encoding the missing SMN protein. As of the data cutoff, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort.

In the high-dose START cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. [51]  Of the 12 patients who had received the high dose, 11 sat unassisted, nine rolled over, 11 fed orally and could speak, and two walked independently. Elevated serum aminotransferase levels occurred in four patients and were attenuated by prednisolone.

Interim data analysis from the ongoing phase 3 STR1VE trial determined that 21 of 22 (95%) patients were alive and event-free. [50]  The median age was 9.5 months, with six of seven (86%) patients aged 0.5 months or older surviving event-free. Interim results also showed ongoing improvement of motor milestones (eg, holding head erect, rolling over, sitting without support).


Risdiplam, approved by the FDA in August 2020, is a survival of an SMN2 mRNA splicing modifier designed to treat mutations in chromosome 5q that lead to SMN protein deficiency. It is indicated for type I, II, and III SMA in adults and children aged 2 months or older. Approval was supported by results from several phase 3 trials (including FIREFISH [52]  and SUNFISH [53] ). 

In FIREFISH, an open-label two-part pivotal clinical trial in infants aged 2-7 months with type I SMA, 41% of infants (7/17) achieved ability to sit without support for at least 5 seconds, and 90% (19/21) were alive without permanent ventilation at 12 months. [52]  After a minimum of 23 months of treatment and reaching an age of 28 months or older, 81% (17/21) of all patients were alive without permanent ventilation. 

In SUNFISH, a two-part double-blind placebo-controlled pivotal clinical trial in children and young adults (aged 2-25 years) with type II or III SMA, a clinically meaningful and statistically significant improvement in motor function was observed among children and adults, as measured by a change from baseline in the MFM-32 total score. [53]  Upper-limb motor function as compared with baseline, as measured by the Revised Upper Limb Module (RULM), a secondary independent motor function endpoint of the study, also showed statistically significant improvement.

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