Spinal muscular atrophy: From approved therapies to future therapeutic targets for personalized medicine

Abstract

Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease that, in the most severe cases and when left untreated, leads to death within the first two years of life. Recent therapeutic advances have given hope to families and patients by compensating for the deficiency in survival motor neuron (SMN) protein via gene therapy or other genetic manipulation. However, it is now apparent that none of these therapies will cure SMA alone. In this review, we discuss the three currently licensed therapies for SMA, briefly highlighting their respective advantages and disadvantages, before considering alternative approaches to increasing SMN protein levels. We then explore recent preclinical research that is identifying and targeting dysregulated pathways secondary to, or independent of, SMN deficiency that may provide adjunctive opportunities for SMA. These additional therapies are likely to be key for the development of treatments that are effective across the lifespan of SMA patients.

Keywords: SMN; apoptosis; cytoskeleton; gene therapy; neuromuscular junction; neuroprotection; splicing modulator; ubiquitination.

Graphical abstract

Figure 1

Schematic of the main SMN-independent potential therapeutic targets Because of the diverse cellular roles and ubiquitous expression of SMN, SMN deficiency leads to changes in numerous cellular processes and organs, which have been identified as possible therapeutic targets. For clarity, we classified these targets into cellular pathway degradation, neuroprotection, cytoskeleton, muscle, and neuromuscular junction, but some therapies may span over multiple targets.