Spinal Muscular Atrophy (SMA)

In recent years, the US Food and Drug Administration has approved 3 disease-modifying treatments for spinal muscular atrophy (SMA): nusinersen (Spinraza®), onasemnogene abeparvovec-xioi (Zolgensma®), and risdiplam (Evrysdi™). In addition, a number of new therapies with various mechanisms of action are currently being investigated for the treatment of SMA, a rare genetic disorder caused by mutations or deletions in the SMN1 gene.

Antisense Oligonucleotides

Antisense oligonucleotides (ASOs) are possible treatments for SMA that “fix” the mRNA molecules produced by the SMN2 gene. The SMN2 gene codes for SMN protein and serves as a backup for the SMN1 gene in patients with SMA. Most of the mRNA derived from SMN2 lacks exon 7, which results in the formation of truncated forms of SMN protein. ASOs may correct this error and thereby increase the amount of viable SMN protein encoded by SMN2. Nusinersen is an ASO.

An ASO that was in preclinical development was used to target an inhibitory molecule called gene-repressive complex (PRC2). The oligonucleotide could sterically inhibit PRC2 from binding to and inhibiting expression of the SMN2 gene. Results of preclinical work in cells from patients with SMA showed that treatment with the oligonucleotide resulted in increased production of SMN.1 The company that was developing the treatment, RaNA Therapeutics, has been rebranded as Translate Bio2 and does not appear to be prioritizing this treatment anymore.3

E1v1.11 is a new ASO that is being developed by Shift Pharmaceuticals. It is a phosphorodiamidate morpholino oligomer (PMO) that blocks the binding of a regulatory protein called Element1 (E1). By blocking Element 1, E1v1.11 increases the production of SMN protein encoded by the SMN2 gene. Preclinical research in murine models of severe SMA found E1v1.11 could increase length of survival.4 This treatment received Orphan Drug Designation from the FDA in March 2020.5

Gene Therapy

Onasemnogene abeparvovec, which utilizes an adeno-associated virus serotype 9 (AAV9) vector to insert a working copy of DNA that codes for the SMN protein, was the first gene therapy to gain FDA approval for use in patients with SMA. 

In addition, clustered regularly interspaced short palindromic repeats (CRISPRs) are being investigated to develop a new method of gene therapy. In 2 studies conducted at different research centers in China, CRISPRs were used to modify SMN production from the SMN2 gene. One study used CRISPR/Cpf1 to modify the SMN2 gene to be more similar to the SMN1 gene. This technique was able to increase SMN expression in induced pluripotent stem cells (iPSCs) from a patient with SMA.6

Another study used CRISPR/Cas9 to modify the code of 2 intronic splicing silencers to enhance the inclusion of exon 7 in mRNA from the SMN2 gene. Results from this study showed increased survival of iPSCs, as well as transgenic SMA.7

However, both treatments are still in the early phases of development and will require further study before they are ready for clinical trials.

Therapy to Increase SMN2 Expression

Branaplam (LMI070), from Novartis, is a small-molecule therapy similar to risdiplam. The treatment, which is administered orally once a week, acts as an RNA splicing modulator. Branaplam is currently being investigated in a Phase 1/2 clinical trial (NCT02268552) that aims to recruit 40 patients who have SMA type 1 with 2 copies of the SMN2 gene.

Preliminary results in 13 patients showed improved scores on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND)8 and the Hammersmith Infant Neurological Exam (HINE)9, in addition to improvements in breathing and feeding tasks in some patients. However, 5 patients died because of disease progression.10 The study was halted for 2 years after adverse reactions were detected in animal models. However, it has since been resumed in Europe and is estimated to be completed in 2023. Branaplam is also being investigated for the treatment of Huntington’s disease.11

Myoprotective/Enhancing Therapies

Reldesemtiv (formerly CK-2127107) is a fast skeletal muscle troponin activator (FSTA) that slows the release of calcium from the troponin complex, enhancing muscle contractility.12 It has been studied in a Phase 2 trial (NCT02644668) of 70 patients aged 12 years or older with SMA type 2, 3, or 4. Study results showed statistical increases in 6-minute walk time and maximum expiratory pressure.13 The therapy is being developed by Cytokinetics in collaboration with Astellas Pharma. Reldesemtiv is also being investigated in patients with amyotrophic lateral sclerosis (ALS).

Apitegromab (formerly SRK-015) is a myostatin inhibitor developed in the hope of increasing muscle size and strength. It is currently under investigation in a Phase 2 trial, TOPAZ (NCT03921528), of 58 patients with type 2 or 3 SMA. Top-line analysis14 of 12-month data showed no major safety concerns when intravenous doses were administered once every 4 weeks. The results also showed that the majority of patients had stable or increased motor function on the Hammersmith Functional Motor Scale Expanded (HFMSE) or the Revised Hammersmith Scale (RMS). 

Another myostatin inhibitor, BIIB110 (formerly ALG-801), is being studied in a Phase 1a trial.15 The treatment was originally being developed by AliveGen before it was purchased by Biogen in 2018.16 

Stem Cell Therapy

Stem cell therapy is another potential treatment for SMA. The research is still in the preclinical testing phase, but a study has shown that the administration of human amniotic fluid stem cells (hAFSCs) to a murine model of SMA type 3 in utero can successfully treat the disease.17 The survival rate was improved in mice injected with hAFSCs in utero (15 of 16) in comparison with untreated controls (10 of 16). The mice also demonstrated significantly better performance on 3 behavioral tasks at certain time points, in comparison with untreated controls; measurements included time holding onto a Rotarod rotating at increasing speed, grasp force, and angle reached before the mouse slipped off a tilting wooden platform.

Reviewed by Michael Sapko, MD on 7/1/2021


1. RaNA Therapeutics presents data on advances in RNA therapy targeting spinal muscular atrophy. News release. BioSpace. March 23, 2016. 

2. RaNA therapeutics relaunches as Translate Bio to advance RNA therapeutics. Translate Bio. News release. June 27, 2017.

3. MRNA therapeutics and vaccines. Translate Bio. June 16, 2017. Accessed April 22, 2021.

4. Osman EY, Washington CW 3rd, Kaifer KA, et al. Optimization of morpholino antisense oligonucleotides targeting the intronic repressor element1 in spinal muscular atrophy. Mol Ther. 2016;24(9):1592-1601. doi:10.1038/mt.2016.145

5. Shift Pharmaceuticals receives US FDA Orphan Drug Designation for their lead compound for SMA. Spinal Muscular Atrophy UK. March 9, 2020. Accessed June 7, 2021.

6. Zhou M, Hu Z, Qiu L, et al. Seamless genetic conversion of SMN2 to SMN1 via CRISPR/Cpf1 and single-stranded oligodeoxynucleotides in spinal muscular atrophy patient-specific induced pluripotent stem cells. Hum Gene Ther. 2018;29(11):1252-1263. doi:10.1089/hum.2017.255

7. Li J-J, Lin X, Tang C, et al. Disruption of splicing-regulatory elements using CRISPR/Cas9 to rescue spinal muscular atrophy in human iPSCs and mice. Natl Sci Rev. 2020;7(1):92-101. doi:10.1093/nsr/nwz131

8. Glanzman AM, Mazzone E, Main M, et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord. 2010;20(3):155-161. doi:10.1016/j.nmd.2009.11.014

9. Romeo DM, Ricci D, Brogna C, Mercuri E. Use of the Hammersmith Infant Neurological Examination in infants with cerebral palsy: a critical review of the literature. Dev Med Child Neurol. 2016;58(3):240-45. doi:10.1111/dmcn.12876

10. Charnas L, Voltz E, Pfister C, et al. Safety and efficacy findings in the first-in-human trial (FIH) of the oral splice modulator branaplam in type 1 spinal muscular atrophy (SMA): interim results. Neuromuscul Disord. 2017;27:S207-8. doi:doi.org/10.1016/j.nmd.2017.06.411

11. Novartis receives US Food and Drug Administration (FDA) Orphan Drug Designation for branaplam (LMI070) in Huntington’s disease (HD). News release. Novartis. October 21, 2020.

12. Reldesemtiv. Cytokinetics. 2020. Accessed June 7, 2021.

13. Rudnicki SA, Andrews JA, Duong T, et al. Reldesemtiv in patients with spinal muscular atrophy: a phase 2 hypothesis-generating study. Neurotherapeutics. Published online February 23, 2021. doi:10.1007/s13311-020-01004-3

14. Scholar Rock announces positive 12-month top-line results from the TOPAZ phase 2 clinical trial evaluating apitegromab in patients with type 2 and type 3 spinal muscular atrophy (SMA). News release. BioSpace. April 6, 2021.

15. Chen T-H. New and developing therapies in spinal muscular atrophy: From genotype to phenotype to treatment and where do we stand? Int J Mol Sci. 2020;21(9):3297. doi:/10.3390/ijms21093297

16. Biogen Q2 2018 revenues increase 9% to $3.4 billion. News release. Biogen. July 24, 2018.17. Shaw SW, Peng S-Y, Liang C-C, et al. Prenatal transplantation of human amniotic fluid stem cell could improve clinical outcome of type III spinal muscular atrophy in mice.Sci Rep. 2021;11(1):9158. doi:10.1038/s41598-021-88559-z