Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by loss of speech, EEG abnormalities, seizures, motor impairments, and severe intellectual disabilities. Unfortunately, there are no treatments for its core symptoms. PTHS is caused by haploinsufficiency of TCF4, a transcription factor that regulates hundreds of genes, making it nearly impossible to therapeutically address the full phenotypic spectrum of the disorder by targeting downstream molecular pathways. Ideally, PTHS would be treated at its roots, by augmenting the expression of the intact TCF4 gene copy to normalize gene expression levels. We hypothesize that small molecules capable of upregulating TCF4 expression during early postnatal development, and perhaps into adulthood, will correct PTHS phenotypes. To develop an informed therapeutic intervention strategy and to identify TCF4 activators for eventual clinical trials, we will complete three Aims: (1) establish the biodistribution of TCF4 to guide therapeutic delivery, (2) assess phenotypic rescue with early- or late-onset normalization of TCF4, and (3) identify approaches to increase TCF4 levels. We have developed and validated powerful tools to facilitate each of these Aims, which are integral to guiding the clinical development of genetic normalization treatments for PTHS.
Loss of one copy of the TCF4 gene causes Pitt-Hopkins syndrome, a neurodevelopmental disorder associated with severe intellectual disability, lack of speech, EEG abnormalities, hyperactivity, and seizures. Pitt-Hopkins syndrome could be treated by normalizing TCF4 expression. We will optimize such approaches by characterizing the expression pattern of TCF4, establishing the therapeutic efficacy of normalizing TCF4 in neonates and adulthood, and identifying approaches to increase TCF4 expression.
