Gene editing as a new therapeutic era for SMA

SMA (Spinal muscular atrophy) refers to a group of autosomal recessive neuromuscular disorders whichdegenerates the anterior horn cells of the spinal cord, leading to muscular weakness and death in infancy with anincidence of about 1/6000–10,000 live births. SMA classification (SMA I, SMAII, SMAIII, SMA IV) is based onthe age of onset, maximum motor function attained, and survivorship. SMA is caused by recessive mutations inthe SMN1 gene on chromosome 5q. The primary modulator of the clinical phenotype is the paralogue geneSMN2 which differs from SMN1 by a critical SNP in exon 7 (C to T). A potential treatment strategy for SMA isto increase SMN levels in the affected tissues, hence modifiers of SMN2-alternative splicing have provedtherapeutic efficacy in animal models but the ideal therapeutic approach for SMA is to correct causal mutations.This highly permanent approach would avoid the possibility of insertional mutations associated with viral genedelivery. Engineered nucleases, including meganucleases, zinc finger nucleases (ZFNs), transcription activatorlikeeffector nucleases (TALENs), and the CRISPR-Cas9 system, have been developed in recent years to modifythe genomes. Among these nucleases, the Cas9 nuclease, which recognizes target DNA according to Watson-Crick base pairing between its guide RNA and DNA, is the simplest one to implement and quickly become themost powerful tool for genome editing. Two main strategies existed in gene editing of SMA: SMN1_exon7addition/correction by promoting homology-driven DNA repair and SMN2_intron7_ intronic-splicing-silencer(ISS-N1) mutation and correction of SMN2 aberrant splicing, by exploiting the non-homologous end-joining(NHEJ) pathway.

کلیدواژه ها:

SMA ، SMN1 ، SMN2 ، Gene editing ، Engineered nuclease ، CRISPR