Pitt-Hopkins Syndrome: studies on pathophysiology and genetic therapy using patient-derived cells and cerebral organoids

Abstract

Autism-spectrum disorders impact millions of individuals worldwide, representing a heavy toll on affected children, their families, and the health system. Pitt-Hopkins Syndrome (PTHS), one of the few diseases in the spectrum with known genetic etiology, is characterized by severe intellectual disability and cognitive impairment, pronounced developmental and motor delays, absence of spoken language, repetitive behaviors, peculiar facial gestalt, and gastrointestinal manifestations. While a genetic link between mutations in the gene TCF4 and PTHS is well established, its pathophysiology is mostly unknown, which has prevented the development of therapeutic strategies. The goals of this application are: (a) to analyze cells and organoids derived from Pitt-Hopkins patients to define the pathological consequences of clinically relevant TCF4 mutations; and (b) to provide proof-of-concept that correctional genetic strategies can be used to fix TCF4 expression, an approach that could eventually be used as therapy for PTHS. Our central hypothesis is that mutations in TCF4 impair specific cell types, affecting neural development and causing PTHS phenotypes. Such hypothesis is based on preliminary findings that (a) the expression of TCF4 is high in neural progenitor cells, (b) progenitors exhibit senescence and decreased proliferation, accompanied by downregulation of Wnt signaling, and (c) PTHS brain organoids fail to develop normal anatomically organized progenitor structures and cortical neurons, and display severely impaired firing properties. Our anticipated results include the identification of specific altered molecular and cellular pathways and the testing of correctional genetic strategies for PTHS. (AU)