Nusinersen in Spinal Muscular Atrophy: What is Still Unclear

In 2016, nusinersen, or Spinraza, became the first drug for spinal muscular atrophy (SMA) ever approved by the U.S. Food and Drug Administration.1 The drug acts to combat low survival motor neuron (SMN) protein in the central nervous system by correcting the splicing of SMN2 mRNA.2 Though the introduction of nusinersen has been a major step forward in SMA and has been associated with growing knowledge about both the disease and the intervention, there is much still to be learned about the drug and its potential to help SMA patients.

Individual Differences in Response to Nusinersen

Clinical trials have demonstrated that there is a wide variation in response to nusinersen.3 While some response differences may be attributed to factors like patient age and how long a patient has had the disease, there appear to be unidentified factors contributing to the way that individual SMA patients react to the therapy. Determining what makes SMA patients more or less likely to benefit from nusinersen treatment could be valuable in developing a plan for therapy. 

Using biomarkers, like full-length SMN RNA or microRNA, represents one strategy for predicting outcomes related to the use of nusinersen.4 Another factor that may affect outcomes related to the use of nusinersen is the simultaneous use of other interventions. Further research is needed to clarify the ways in which nusinersen may interact with other therapies and if certain combinations of drugs may work synergistically to help those with SMA.

Potential of Nusinersen in the Most and Least Severe Forms of SMA

There do not appear to be any data published on the use of nusinersen in SMA type 0 or SMA type 4 patients.5 Given the severity of SMA type 0, parents of these patients tend to decline treatment once they understand the disease and its prognosis. Though it may be unlikely that a clinical study of the effects of nusinersen in SMA type 0 will be successfully completed, case studies that report on the use of the therapy in this patient population would be valuable for determining if these patients could potentially benefit from nusinersen and what the benefits may be.

In those with less severe forms of the disease, such as SMA type 3 and SMA type 4, the cost-benefit analysis of using nusinersen is different from this type of analysis for SMA type 1 and SMA type 2 patients,6 which may explain why there are fewer data on the use of nusinersen in these less severe cases. Nonetheless, just as with SMA type 0 patients, case studies on how nusinersen influences symptoms in those with less severe forms of SMA will provide useful information for treating these populations and for performing the cost-benefit analysis of trying nusinersen as an SMA therapy.

Long-Term Effects of Nusinersen in Pre-Symptomatic and SMA Type 1 Patients

Though the data on nusinersen in pre-symptomatic patients and patients with SMA type 1 are relatively abundant, our understanding of the long-term effects of the drug on these patients lacks robustness. Given how new the drug is, there has not yet been sufficient time for a comprehensive evaluation of the drug’s long-term effects. However, the data collected thus far do provide some important insights. For instance, it appears that pre-symptomatic patients treated before the onset of symptoms fare better than those who wait until symptoms begin to start nusinersen.7 

Still, many questions remain. For instance, research will hopefully provide information on the chances that SMA type 1 patients taking nusinersen will achieve major milestones like walking or living without the support of a ventilator.5 With time, more data will be collected on the impact of nusinersen on distinct SMA patient populations, and these data will help to inform healthcare providers, patients, parents, and caregivers as they navigate therapeutic options.


1. 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

2. Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR. Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the  exon. PLoS Biol. 2007;5(4):e73. doi:10.1371/journal.pbio.0050073

3. 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

4. Magri F, Vanoli F, Corti S. miRNA in spinal muscular atrophy pathogenesis and therapy. J Cell Mol Med. 2018;22(2):755-767. doi:10.1111/jcmm.13450

5. Gidaro T, Servais L. Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps. Dev Med Child Neurol. 2019;61(1):19-24. doi:10.1111/dmcn.14027

6. Michelson D, Ciafaloni E, Ashwal S, et al. Evidence in focus: Nusinersen use in spinal muscular atrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;91(20):923-933. doi:10.1212/WNL.0000000000006502

7. Bertini E et al. Efficacy and safety of nusinersen in infants with presymptomatic spinal muscular atrophy (SMA): Interim results from the NURTURE study. Eur J Paediatr Neurol. 2017;21:e14.