PROJECT SUMMARY The identification of hundreds of genes associated with autism and related neurodevelopmental diseases (ASD/NDDs) in recent years has created and opportunity to leverage genetic discoveries into therapeutics for these disorders. Classically ASD/NDDs were assumed to be intractable due to disrupted development in utero, but studies in mice have demonstrated that restoring gene activity after birth can likely ameliorate phenotypes in some prominent ASD/NDDs. These findings create an imperative to systematically test the feasibility of genetically targeted therapies across ASD/NDDs with distinct genetic causes, but limited studies of this type have been carried out to date. A major class of disorders that has yet to be investigated in this paradigm is ASD/NDD caused by mutation of “epigenetic writer” enzymes. These enzymes chemically modify chromatin and DNA to control gene expression during development and throughout life. While the important potential role of these genes in early cell fate and patterning has suggested it will be it difficult to correct defects after altered development, recent studies have uncovered postnatal functions for these factors that are likely to be drivers of phenotypes in ASD/NDD. Therefore, in the proposed studies we will develop enabling mouse transgenic reagents to investigate the tractability of genetic rescue of ASD/NDDs caused by mutation of epigenetic writers. Our previous studies that have uncovered postnatal functions for the ASD/NDD-associated writer DNA methyltransferase 3A (DNMT3A) and defined robust phenotypes in heterozygous mutant mice the mimic human DNMT3A ASD/NDD mutations. We will therefore investigate the tractability of genetic reinstatement of the DNMT3A gene for rescue of molecular and organismal deficits in mice. We will implement a newly-established DNMT3A conditional genetic rescue strain to test the requirements for timing of DNMT3A reinstatement necessary to rescue molecular deficits in vivo (Aim 1). We will then perform proof-of-principle studies to investigate the degree to which behavioral and physiological function can be rescued by gene reactivation (Aim 2). Together these studies will establish enabling technologies and essential proof-of-principle findings to guide future large-scale development gene targeted therapeutics in DNMT3A disorders. Furthermore, by assessing the tractability of reinstatement for epigenetic writers in ASD/NDD, our studies can motivate therapeutic research efforts across a broad class of genetic causes for these disorders, advancing toward treatments for these devastating conditions.