T.P.7 Small molecule compounds correct alternative splicing of the SMN2 gene and restore SMN protein expression and function

Abstract Spinal muscular atrophy (SMA) is caused by the reduced expression of the survival of motor neuron (SMN) protein due to the loss of functional SMN1 gene and alternative splicing of exon 7 in the SMN2 gene. We are pursuing innovative drug discovery strategies aimed at restoring the production of the SMN protein by modulating SMN2 alternative splicing. Panels of cell based assays and animal models have been established and optimized to assess the effects of compounds on the splicing of SMN mRNA and the production and function of SMN protein. Using these assays, small molecules have been identified and developed that increase the inclusion of exon 7 into SMN2 mRNA and efficiently correct the splicing defect of SMN2. As a result of the increase of exon 7 inclusion, SMN protein level in SMA patient cell lines and mouse models is elevated by several fold and can even exceed that in healthy SMA carriers. These small molecules extend the lifespan of severely affected delta7 SMA mice tenfold (>150 days) and result in striking gains in motor function relative to untreated mice that live an average of 14 days. Moreover, these molecules demonstrate efficacy when treatment of delta7 SMA mice is initiated after disease onset. Lead compounds from this program are undergoing further characterization and chemical optimization with the ultimate goal of identifying molecules for preclinical and clinical development.