Binding to SMN2 pre-mRNA-Protein complex elicits specificity for small molecule splicing modifiers

Small molecule splicing modifiers have been extensively described which target the generic splicing machinery and thus have low target specificity. We have identified potent splicing modifiers with unprecedented high selectively, correcting the splicing deficit of the SMN2 (survival motor neuron 2) gene in Spinal Muscular Atrophy (SMA). Here we show that they directly bind to two sites of the SMN2 pre-mRNA, thereby stabilizing a novel ribonucleoprotein (RNP) complex in the SMN2 gene that is critical for the high target specificity of these small molecules over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work may have wide-ranging consequences for further research to identify small molecules that target splicing correction of specific genes by interacting with tertiary RNA structures. mRNA profiling of type I SMA fibroblasts treated with NVS-SM1