Identification of Molecular Targets for Pitt-Hopkins Syndrome Treatments

PI: Benjamin Philpot, PhD

Institution: University of North Carolina, Chapel Hill

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Pitt-Hopkins Syndrome (PTHS) is a rare neurodevelopmental disorder marked by severe intellectual disability, absent communication, and breathing abnormalities. PTHS is accompanied by neurological symptoms, including epileptic seizures, abnormal EEG signatures, microcephaly, and anatomical disruptions of the hippocampus and corpus callosum. PTHS is caused by haploinsufficiency or loss of function of the gene TCF4 (transcription factor 4), but the role of TCF4 in the early and continued development of the nervous system, and how the pathophysiology of PTHS emerges from dysregulation of TCF4 function remain largely unknown. This mechanistic gap in our understanding of PTHS impedes the development of treatments for the disorder. To develop rational PTHS therapeutics, we proposed to (1) examine the synaptic basis for Pitt-Hopkins pathophysiology and (2) develop a novel mouse model to guide future drug development.  With our pilot funding we discovered compelling evidence that perturbation of TCF4 function results in an increase in NMDA receptor function within the hippocampus.  We also developed a conditional TCF4 mouse that will allow us to establish the critical period for TCF4 expression, thus helping to define an optimal therapeutic intervention window.