Résumé :
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Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutation of the SMN1 gene that results in reduced full-length SMN protein abundance. All patients have SMN2, a centromeric copy of the gene that predominantly encodes a truncated version of the protein as a result of the skipping of exon 7 in the mRNA. A small amount of full-length protein is made from SMN2, and therefore, disease severity is inversely correlated with SMN2 gene copy number. Increasing SMN by promoting exon 7 splicing in RNA from SMN2 is a promising therapeutic strategy for SMA. We have recently identified a compound, PTK-SMA1, that exhibits such activity. PTK-SMA1 is a proprietary tetracycline-like molecule developed by Paratek Pharmaceuticals. Specificity and mechanistic studies of PTK-SMA1 activity indicate that the compound targets splice factors that regulate exon 7 inclusion in a relatively specific manner. Our results suggest that the compound will have minimal off-target effects on global alternative splicing when introduced to patients, further supporting the potential utility of PTK-SMA1 as an SMA therapeutic. We have also identified a feedback loop in SMN expression by which low SMN protein levels exacerbate SMN exon 7 skipping, thus leading to a further reduction in SMN protein. These results imply that a modest increase in SMN protein abundance, as achieved with PTK-SMA1, will result in a disproportionately large increase in SMN expression. This feedback loop has important implications for any approach that results in an increase in SMN protein abundance. Overall, our results confirm the promise of PTK-SMA1 as a possible therapeutic for SMA, and also demonstrate the ability to target the splicing reaction for the treatment of SMA. In light of this, we have initiated studies to systematically analyze the role of specific classes of splicing factors in the regulation of exon 7 splicing, in order to identify proteins that could be targeted in the search for novel SMA therapeutics.
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