For individuals carrying a genetic risk factor that inactivates one of two gene copies, as is often the case for mutations in CHD8, amplifying the expression of the remaining functional copy is a potential therapeutic target. In the current proposal, Rebecca Muhle plans to use high-throughput in vitro screening assays to discover compounds that affect the endogenous expression of CHD8 and to subsequently test validated compounds in a mouse model of Chd8 haploinsufficiency.

Genetics studies have identified many high-confidence risk genes for autism spectrum disorder (ASD). An important next step is to test the efficacy of different therapeutic approaches tailored to subtypes of ASD that are associated with mutations in specific risk genes. In the current project, Michael Boland and Wayne Frankel plan to assess the ability of three different genetic therapy strategies to correct multiple phenotypes in neurons derived from human induced pluripotent stem cells and mouse models of STXBP1 haploinsufficiency.