Disease-Modifying Therapies for Treating SMA

Until the approval of nusinersen (Spinraza), treatment for spinal muscular atrophy was largely supportive. While patients with SMA enjoy benefits from respiratory therapy, physical therapy, nutrition support, etc., these therapies are aimed at maximizing residual function and/or relieving symptoms. Spinraza is the first agent that actually targets one of the mechanisms of the disease, namely it corrects SMN2 exon 7 splicings.1 While the approval of nusinersen is an exciting milestone in the treatment of spinal muscular atrophy, it may only be the tip of the iceberg. Several other disease-modifying treatments for SMA are currently in clinical trials.2

Most disease-modifying treatments in development for SMA target one of the well-known pathologies in the disease: dramatically reduced levels of survival motor neuron (SMN) protein. Spinraza is the principal example of drugs in this group. Spinraza is an antisense oligonucleotide that selectively binds to the ISS-N1 regulatory motif in the intron downstream of exon 7 on SMN2 pre-mRNA. The oligonucleotide prevents the binding of proteins and factors that would otherwise suppress the expression of normal SMN protein. Consequently, nusinersen promotes the expression of full-length SMN protein.1

Another approach to increasing SMN protein levels is by using gene therapy to restore SMN gene expression. AVXS-101 is a gene therapy product that uses adeno-associated virus (AAV) to replace the SMN gene. After showing success in mouse3 and nonhuman primate studies4, AVXS-101 was tested in a phase 1 clinical trial. The product was designed to deliver two copies of the SMN2 gene through self-complementary AAV. Initial results of this gene therapy approach suggest AVXS-101 was able to increase survival, and help patients reach motor milestones and achieve oral feeding.5 

Branaplam and RG7916 are small molecule, oral therapies that modify the way in which SMN2 mRNA is spliced, ultimately resulting in increased levels of full-length SMN2 mRNA and SMN protein.2 The initial branaplam clinical trial temporarily met with difficulty when a possible nerve injury signal was reported during toxicology testing; however, this has apparently been resolved since the phase 1 and 2 trials have resumed.6 The other agnet in this class, RG7916, appears to be safe, well tolerated, and apparently increases the levels of full-length SMN2 mRNA.7 A pivotal phase 2 trial is now underway in non-ambulatory SMA type 2 and SMA type 3 patients to test efficacy and safety.

Valproic acid, widely known as an anticonvulsant, has also been trialed as a way to up regulate SMN2 transcription by inhibiting histone deacetylase activity.8 The clinical trial results of valproic acid alone have been disappointing. Moreover, adding L-carnitine to valproic acid in an attempt to block hepatotoxicity of the latter has yielded similar lackluster results. While interested parties are continuing to look for ways to test valproic acid in a subset of SMA patients that may be responsive to the anticonvulsant, this agent is generally considered less promising than the others described.

Increasing the expression of full-length SMN protein is only one target of disease modifying SMA therapy. Olesoxime—plus a number of preclinical agents—are being developed as general neuroprotective agents that may be of use in spinal muscular atrophy.2 Olesoxime binds to the mitochondrial permeability pore and prevents excess transmembrane flow of substances when exposed to cellular stress.9 In other words, olesoxime does not affect the SMN protein, but attempts to block one of the main consequences of insufficient SMN protein levels within cells that leads to cell death. The molecule was tested in a randomized, double-blind, placebo-controlled phase 2 clinical trial in SMA type 2 and non-ambulatory SMA type 3 patients of various ages.10 Olesoxime significantly supported motor function compared to placebo, with the greatest benefit observed in the high-dose cohort and children aged 6 to 15. Participants in this trial enrolled over to an open label, single arm study to evaluate safety and efficacy.

The final major approach to directly treating SMA is to support muscle function. Of this type of disease-modifying agent, CK-107 and SRK-015 have proceeded furthest in development. CK-107 is a troponin complex activator that increases muscular force with submaximal motor nerve stimulation.2,11 CK-107 was well tolerated in a phase 1 trial among healthy volunteers, and is now being tested in a double-blind, randomized, placebo-controlled phase 2 clinical trial. SRK-015 is a myostatin inhibitor that increases muscle mass and muscular force. Clinical trials of SRK-015 have been announced, and the agent may be positioned as a stand-alone therapy or used in combination with disease-modifying agents that target SMN protein levels.2


1. Singh NN, Howell MD, Androphy EJ, Singh RN. How the Discovery of Iss-N1 Led to the First Medical Therapy for Spinal Muscular Atrophy. Gene Ther. 2017;24(9):520-526. doi:10.1038/gt.2017.34 

2. 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 

3. Passini MA, Bu J, Roskelley EM, et al. Cns-Targeted Gene Therapy Improves Survival and Motor Function in a Mouse Model of Spinal Muscular Atrophy. J Clin Invest. 2010;120(4):1253-1264. doi:10.1172/JCI41615 

4. Bevan AK, Duque S, Foust KD, et al. Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders. Mol Ther. 2011;19(11):1971-1980. doi:10.1038/mt.2011.157 

5. Mendell JR, Al-Zaidy S, Shell R, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1713-1722. doi:10.1056/NEJMoa1706198 

6. 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. Neuromuscular Disorders. 2017;27:S207-S208. doi:10.1016/j.nmd.2017.06.411 

7. Mercuri E, Kirschner J, Baranello G, et al. Clinical Studies of Rg7916 in Patients with Spinal Muscular Atrophy: Sunfish Part 1 Study Update. Neuromuscular Disorders. 2017;27:S209. doi:10.1016/j.nmd.2017.06.415 

8. Swoboda KJ, Scott CB, Reyna SP, et al. Phase Ii Open Label Study of Valproic Acid in Spinal Muscular Atrophy. PLoS One. 2009;4(5):e5268. doi:10.1371/journal.pone.0005268 

9. Sunyach C, Michaud M, Arnoux T, et al. Olesoxime Delays Muscle Denervation, Astrogliosis, Microglial Activation and Motoneuron Death in an Als Mouse Model. Neuropharmacology. 2012;62(7):2346-2352. doi:10.1016/j.neuropharm.2012.02.013 

10. Bertini E, Dessaud E, Mercuri E, et al. Safety and Efficacy of Olesoxime in Patients with Type 2 or Non-Ambulatory Type 3 Spinal Muscular Atrophy: A Randomised, Double-Blind, Placebo-Controlled Phase 2 Trial. Lancet Neurol. 2017;16(7):513-522. doi:10.1016/S1474-4422(17)30085-6 

11. Hwee DT, Kennedy AR, Hartman JJ, et al. The Small-Molecule Fast Skeletal Troponin Activator, Ck-2127107, Improves Exercise Tolerance in a Rat Model of Heart Failure. J Pharmacol Exp Ther. 2015;353(1):159-168. doi:10.1124/jpet.114.222224