Pharmacotherapy for Spinal Muscular Atrophy in Babies and Children: A Review of Approved and Experimental Therapies.

Spinal muscular atrophy (SMA) is an autosomal recessive degenerative neuromuscular disorder characterized by loss of spinal motor neurons leading to muscle weakness and atrophy that is caused by survival motor neuron (SMN) protein deficiency resulting from the biallelic loss of the SMN1 gene. The SMN2 gene modulates the SMA phenotype, as a small fraction of its transcripts are alternatively spliced to produce full-length SMN (fSMN) protein. SMN-targeted therapies increase SMN protein; mRNA therapies, nusinersen and risdiplam, increase the amount of fSMN transcripts alternatively spliced from the SMN2 gene, while gene transfer therapy, onasemnogene abeparvovec xioi, increases SMN protein by introducing the hSMN gene into various tissues, including spinal cord via an AAV9 vector. These SMN-targeted therapies have been found effective in improving outcomes and are approved for use in SMA in the US and elsewhere. This article discusses the clinical trial results for SMN-directed therapies with a focus on efficacy, side effects and treatment response predictors. It also discusses preliminary data from muscle-targeted trials, as single agents and in combination with SMN-targeted therapies, as well as other classes of SMA treatments.