New Approaches and Approved Drugs in Spinal Muscular Atrophy (SMA) Treatment

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease lead to by deletions or mutations in the survival motor neuron (SMN1) gene. SMA is the most common inherited cause of childhood mortality. SMN1 exists as a single copy in the genome of all eukaryotic organisms. Genomic duplication causes a second gene, SMN2 in humans. Approximately 95% of SMA patient has homozygous deletions in exon 7 of SMN1. Thus, SMN protein can’t be produced sufficiently. SMN2 produces a small amount functional SMN protein due to substitution (C-T) in exon 7. SMA is classfied into five types (0-IV) based on age of onset, severity of motor decline and life expectancy. Type I (Werding-Hoffmann) is the most severe and primarily affects infants. Phenotypic variability in SMA patients is also associated with the copy number of the SMN2 gene. The copy number of SMN2 correlates with the severity of the disease. The SMN protein has a key regulator roles such as mRNA transport, RNA metabolism in neuronal cells. Currently, the main target for SMA treatment is to increase SMN protein level in motor neuron cells with small molecules, oligonucleotides, and gene replacement. Stem cell studies are performed as well for SMA treatment. FDA has approved three drugs in the SMA treatment since 2016. These drugs are nusinersen (oligonucleotide), onasemnogene abeparvovec-xioi (gene therapy), and risdiplam (SMN2 gene modifier). Early diagnosis has important role in drugs efficacy. Motor neuron dysfunctions may be reversible when SMN-dependent therapeutic approaches can be applied presymptomatically.