New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?

Abstract

Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficient copy of the gene. A genotype-phenotype correlation suggests that SMN2 is a potent disease modifier for SMA, which also represents the primary target for potential therapies. Increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple therapeutic approaches. Until the end of 2016, no cure was available for SMA, and management consisted of supportive measures. Two breakthrough SMN-targeted treatments, either using antisense oligonucleotides (ASOs) or virus-mediated gene therapy, have recently been approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs and thereby improve motor function and survival. However, neither therapy currently provides a complete cure. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a unique therapeutic solution may not be sufficient. Current approaches under clinical investigation differ in administration routes, frequency of dosing, intrathecal versus systemic delivery, and mechanisms of action. Besides, emerging clinical trials evaluating the efficacy of either SMN-dependent or SMN-independent approaches are ongoing. This review aims to address the different knowledge gaps between genotype, phenotypes, and potential therapeutics.

Keywords: clinical care; novel therapy; spinal muscular atrophy; survival motor neuron protein.

Figure 1

Genetic basis and phenotype-genotype correlation of spinal muscular atrophy (SMA). (A) In a healthy individual, full-length (FL) survival motor neuron (SMN) mRNA and protein arise from the SMN1 gene. Patients with SMA have homozygous deletion or mutation of SMN1 but retain at least one SMN2 (indicated with an asterisk in the solid-border box on the right). However, SMN2 can be dispensable in a healthy individual (indicated with an obelisk in the dotted-border box on the left). This single-nucleotide change in exon 7 (C-to-T) of SMN2 causes alternative splicing during transcription, resulting in most SMN2 mRNA lacking exon 7 (△7 SMN). About 90% of △7 SMN transcripts produce unstable truncated SMN protein, but a minority include exon 7 and code for FL, which maintains a degree of MN survival. (B) A continuous spectrum of phenotypes in SMA. Even with genetic confirmation of SMN1 absence or mutations in all patients, SMA presentation ranges from very compromised neonates (type 0) to adults with minimal manifestations (type 4) depending on the SMN2 numbers and FL SMN produced by each patient and modulated by potential disease modifiers that influence the final phenotype.

Figure 2

Paradigm of multidisciplinary care of SMA, incorporating disease-modifying therapies with supportive care. Novel disease-modifying medications and evolving multidisciplinary supportive management need to occur concomitantly to achieve the best possible outcome for SMA patients.

Figure 3

Therapeutic approaches for SMA. ASO: antisense oligonucleotide; HDACI: histone deacetylase inhibitor; NMJ: neuromuscular junction.