Combined Drug Therapy for Spinal Muscular Atrophy

The first disease-modifying therapy for spinal muscular atrophy (SMA) was approved on December 23, 2016 by the U.S. Food and Drug Administration (FDA), and subsequently by the European Medicines Agency (EMA) on June 1, 2017.1 The drug, nusinersen, or Spinraza, works by increasing protein levels that are deficient in SMA. SMA is caused by the homozygous deletion of the survival motor neuron 1 (SMN1),2  which also results in lowered levels of functional SMN protein.3 Nusinersen increases SMN protein levels by targeting the splicing of a second SMN gene, SMN2.4 Given the success of this modified antisense oligonucleotide (ASO)1 in combatting SMA, it is not surprising that other SMN-targeted strategies are also underway to attempt to help those with the disease.

Despite the safety and clinical efficacy of nusinersen in SMA,5,6 and the apparent necessity of restoring SMN to effectively treat SMN,7,8 the complexity of SMA makes it unlikely that an SMN-targeted therapy can alone reverse or slow the disease.4 Thus, strategies that combine SMN-targeted therapies with SMN-independent approaches are currently being explored. Preclinical studies focused on combined drug therapies for SMA use suboptimal ASO doses because the resulting SMA models appear to be more consistent with what is currently observed in SMA patients receiving nusinersen in clinical trials.9,10 

There is growing evidence to suggest that combining SMN-targeted therapies with approaches that target known modifiers of SMA by, for instance, modifying levels of proteins involved in endocytosis, lead to better outcomes than do SMN-targeted therapies alone.11 The value of combined drug therapy for SMA will be tested in a new trial involving SRK-015, a myostatin inhibitor. In this trial, researchers will compare the impact of the drug on SMA patients currently receiving nusinersen versus those who are not on nusinersen.4 The results from these and future trials will help to clarify the best ways that drugs can be combined to address the specific needs of SMA patients.


1. Paton DM. Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy. Drugs Today (Barc). 2017;53(6):327-337. doi:10.1358/dot.2017.53.6.2652413

2. Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-165.

3. Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997;16(3):265-269. doi:10.1038/ng0797-265

4. Shorrock HK, Gillingwater TH, Groen EJN. Overview of current drugs and molecules in development for spinal muscular atrophy therapy. Drugs. 2018;78(3):293-305. doi:10.1007/s40265-018-0868-8

5. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723-1732. doi:10.1056/NEJMoa1702752

6. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2,  open-label, dose-escalation study. Lancet (London, England). 2016;388(10063):3017-3026. doi:10.1016/S0140-6736(16)31408-8

7. Hua Y, Sahashi K, Rigo F, et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature. 2011;478(7367):123-126. doi:10.1038/nature10485

8. Kariya S, Obis T, Garone C, et al. Requirement of enhanced survival motoneuron protein imposed during neuromuscular  junction maturation. J Clin Invest. 2014;124(2):785-800. doi:10.1172/JCI72017

9. Zhou H, Meng J, Marrosu E, Janghra N, Morgan J, Muntoni F. Repeated low doses of morpholino antisense oligomer: an intermediate mouse model  of spinal muscular atrophy to explore the window of therapeutic response. Hum Mol Genet. 2015;24(22):6265-6277. doi:10.1093/hmg/ddv329

10. Kaifer KA, Villalon E, Osman EY, et al. Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy. JCI insight. 2017;2(5):e89970. doi:10.1172/jci.insight.89970

11. Hosseinibarkooie S, Peters M, Torres-Benito L, et al. The power of human protective modifiers: PLS3 and CORO1C unravel impaired endocytosis in spinal muscular atrophy and rescue SMA phenotype. Am J Hum Genet. 2016;99(3):647-665. doi:10.1016/j.ajhg.2016.07.014