Almost all patients with spinal muscular atrophy (SMA) have deletions of exon 7 of the SMN1 gene.1,2 This genetic deletion leads to dramatic reductions in SMN protein, and the various phenotypic expressions seen in the disease. The timing and severity of SMA symptoms are related to the number of normal copies of a closely related gene the patient possesses, SMN2. Stated another way, the number of SMN2 copies inversely correlates with the severity of weakness and with decreased survival.2 

While the SMN2 gene has the potential to produce SMN protein, the gene product of SMN2 is unstable.3 Thus, endogenous production of SMN2 gene products is insufficient to fully overcome the total loss of SMN1 gene products and subsequent SMN protein loss in people with spinal muscular atrophy.4,5 

Since many patients with SMA have one or two normal copies of SMN2, one therapeutic approach is to use small molecules to enhance the stability of the SMN2 gene product. Indeed, orally administered small molecules were shown to increase the production of full-length SMN2 mRNA and SMN protein in mouse models of SMA.6,7 SMN protein produced by stabilized SMN2 gene products were able to guard against neuromuscular degeneration, improve motor function, and increase survival in an SMN1 knockout mouse (a model of severe SMA).7 

Branaplam (LMI070, NVS-SM1; developed by Novartis) is a small molecule that stabilizes the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein complex.8 Branaplam is currently being tested in an open-label, first-in-human, proof of concept Phase I/II clinical study in infants with SMA type 1 (NCT02268552). Infants enrolled in the study have exactly 2 copies of SMN2. The drug is administered once weekly, and initial phase testing was limited to a 13-week trial period with a 13-month safety and tolerability extension. Branaplam performed reasonably well in early testing.9 Some study participants showed improvement in CHOP INTEND and HINE tests, and were also able to maintain oral feeding and breathing without mechanical support during treatment. On the other hand, five participants died during the course of the trial from disease progression. Adverse events were described as “mostly mild, reversible and manageable.”9 This trial was temporarily paused due to animal toxicity data that emerged during the clinical trial period; however, this issue has apparently been resolved since the larger clinical trial is moving forward. To surveil for the development neurotoxic adverse events, study participants will now undergo periodic nerve testing. It is unclear whether nerve testing will be an ongoing treatment requirement if/when branaplam is approved for use in patients with SMA.


1. Maretina MA, Zheleznyakova GY, Lanko KM, et al. Molecular Factors Involved in Spinal Muscular Atrophy Pathways as Possible Disease-modifying Candidates. Curr Genomics. Aug 2018;19(5):339-355.

2. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat. 2000;15(3):228-237.

3. Ogino S, Wilson RB. Spinal muscular atrophy: molecular genetics and diagnostics. Expert Rev Mol Diagn. Jan 2004;4(1):15-29.

4. Verhaart IEC, Robertson A, Wilson IJ, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy – a literature review. Orphanet J Rare Dis. Jul 4 2017;12(1):124.

5. Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain. Nov 2014;137(Pt 11):2879-2896.

6. Shorrock HK, Gillingwater TH, Groen EJN. Overview of Current Drugs and Molecules in Development for Spinal Muscular Atrophy Therapy. Drugs. Mar 2018;78(3):293-305.

7. Naryshkin NA, Weetall M, Dakka A, et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science. Aug 8 2014;345(6197):688-693.

8. Palacino J, Swalley SE, Song C, et al. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol. Jul 2015;11(7):511-517.

9. 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.