University of North Carolina at Chapel Hill Graduate School
Doi
Abstract
Neurodevelopmental disorders (NDDs) are defined as a group of conditions with onset in the developmental period, including intellectual or language impairments, attention-deficit disorders, and autism spectrum disorder. The United States’ National Health Interview Survey has shown that 1 in 6 children have a developmental disability. The current guidelines for NDDs recommend undergoing an evaluation for genetic etiology and receiving general developmental interventions. Despite no approved treatments for NDDs, development of precision treatment strategies for NDDs has been on the rise. Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by monoallelic mutations or deletions of Transcription Factor 4 (TCF4). A decade of basic research has led to an increased understanding of TCF4, including genetic variants and functional roles in brain development. The development of PTHS mouse models has expanded knowledge in molecular and pathophysiological mechanisms underlying PTHS, underpinning the potential therapeutic opportunities to treat the disorder. However, effective therapeutic approaches for PTHS have not been developed yet. The absence of a validated preclinical pipeline has ultimately impeded successful therapeutic development. Here I propose a genetic normalization strategy to treat PTHS and experimentally demonstrate the feasibility of treating PTHS by normalizing TCF4 expression. Furthermore, I address the challenges faced in developing a rational preclinical pipeline by characterizing the cell type-specific distribution of TCF4 and identifying a feasible intervention window. The studies comprising this dissertation provide an important framework for future rational design of genetic normalization clinical treatments for PTHS.Doctor of Philosoph
