Recent Progress in Gene-Targeting Therapies for Spinal Muscular Atrophy: Promises and Challenges

Abstract

Spinal muscular atrophy (SMA) is a severe genetic disorder characterized by the loss of motor neurons, leading to progressive muscle weakness, loss of mobility, and respiratory complications. In its most severe forms, SMA can result in death within the first two years of life if untreated. The condition arises from mutations in the SMN1 (survival of motor neuron 1) gene, causing a deficiency in the survival motor neuron (SMN) protein. Humans possess a near-identical gene, SMN2, which modifies disease severity and is a primary target for therapies. Recent therapeutic advancements include antisense oligonucleotides (ASOs), small molecules targeting SMN2, and virus-mediated gene replacement therapy delivering a functional copy of SMN1. Additionally, recognizing SMA's broader phenotype involving multiple organs has led to the development of SMN-independent therapies. Evidence now indicates that SMA affects multiple organ systems, suggesting the need for SMN-independent treatments along with SMN-targeting therapies. No single therapy can cure SMA; thus, combination therapies may be essential for comprehensive treatment. This review addresses the SMA etiology, the role of SMN, and provides an overview of the rapidly evolving therapeutic landscape, highlighting current achievements and future directions.

Keywords: SMN protein; SMN2; antisense oligonucleotide (ASO); combination therapy; gene therapy; nusinersen; onasemnogene; risdiplam; small molecule; spinal muscular atrophy (SMA); survival of motor neuron 1 (SMN1).

Figure 1

Genetic basis of SMA. (A) Healthy individuals produce 100% functional SMN protein from their SMN1 genes and only 10% from each of their SMN2 genes. (B) Patients with SMA do not have functional SMN1 and rely on the 10% SMN protein produced by SMN2 due to a C to T transition mutation in exon 7. Most of the SMN protein encoded by SMN2 is rapidly degraded (created with BioRender.com).

Figure 2

Schematic diagram of SMN-dependent (FDA-approved) and SMN-independent therapies (in development) (created with BioRender.com).