Previously, Benjamin Blencowe and colleagues demonstrated that highly conserved, 3-27 nucleotide-long, neuronal microexons have reduced levels of splicing in the brains of more than one-third of analyzed individuals with autism spectrum disorder (ASD)¹. This misregulation correlates significantly with reduced levels of expression of the neuronal-specific Ser/Arg-repeat splicing protein of 100 KDa (nSR100/SRRM4)¹, a splicing regulator that directly activates an extensive neuronal splicing program that includes microexons. Supporting a causative role for nSR100 deficiency in autism, mice haploinsufficient for nSR100 display numerous hallmark features of ASD, including altered social behaviors². Moreover, the levels of nSR100 protein and the splicing of its target microexon programs rapidly decrease following neuronal activation². Collectively, these studies suggest a common mechanistic framework underlying a substantial fraction of ASD cases, namely, that diverse genetic insults that lead to this disorder may converge on nSR100 and its target microexon program as a consequence of causing increased neuronal activity. These results also suggest that drugs capable of selectively stimulating nSR100 activity represent a potential treatment strategy for correcting ASD-associated deficiencies.

Blencowe proposes to develop and apply integrated, high-throughput screening strategies to identify small molecules that specifically stimulate nSR100 activity to restore normal levels of neuronal splicing and that are efficacious for correcting ASD-associated phenotypes. To this end, Blencowe aims to 1) employ multifaceted screens to identify small molecules that promote nSR100 activity and neuronal microexon inclusion; 2) elucidate the global-scale specificity and targets of lead compounds; and 3) evaluate lead compounds for rescue of ASD-related phenotypes in nSR100 haploinsufficient mice. The results of this research are expected to advance our understanding of common molecular mechanisms underlying ASD, as well as the discovery and development of a novel, splicing-directed therapeutic strategy relevant to a substantial fraction of individuals with ASD.