Advances in spinal muscular atrophy therapeutics

Abstract

Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families. Greater knowledge of the molecular basis of SMA pathogenesis has fuelled the development of potential therapeutic approaches, which are illustrated here. Nusinersen, a modified antisense oligonucleotide that modulates the splicing of the SMN2 mRNA transcript, is the first approved drug for all types of SMA. Moreover, the first gene therapy clinical trial using adeno-associated virus (AAV) vectors encoding SMN reported positive results in survival and motor milestones achievement. In addition, other strategies are in the pipeline, including modulation of SMN2 transcripts, neuroprotection, and targeting an increasing number of other peripheral targets, including the skeletal muscle. Based on this premise, it is reasonable to expect that therapeutic approaches aimed at treating SMA will soon be changed, and improved, in a meaningful way. We discuss the challenges with regard to the development of novel treatments for patients with SMA, and depict the current and future scenarios as the field enters into a new era of promising effective treatments.

Keywords: antisense oligonucleotides; gene therapy; neuromuscular disease; spinal muscular atrophy.

Figure 1.

Genetics and therapeutic developments of spinal muscular atrophy (SMA). SMA is caused by mutations, in the survival motor neuron 1 (SMN1) gene that mainly produces full-length SMN that is essential for motor neurons (below right). The human genome harbours a paralogous SMN1 gene, SMN2 (on the left), that differs only by a few nucleotides, and in particular by a C to T transition in exon 7. This base change causes the skipping of exon 7 in most SMN2 transcripts and generates a truncated unstable protein (SMNΔ7) with low levels (approximately 10%) of full-length, functional SMN protein produced (below left). Increasing the full-length SMN protein levels by promoting the inclusion of exon 7 in SMN2 mRNA, that is, with oligonucleotides (on the left) or transferring a wild-type copy of SMN1 through gene therapy (on the right), represents a promising therapeutic approach for SMA. ASO, antisense oligonucleotide.