TCF4 in Pitt-Hopkins syndrome

项目总结 皮特-霍普金斯综合征(PTHS)是一种以言语丧失为特征的神经发育障碍，脑电 异常、癫痫、运动障碍和严重的智力残疾。不幸的是，没有 治疗其核心症状。PTHS由TCF4单倍体不足引起，TCF4是一种转录因子， 调节数百个基因，使其几乎不可能在治疗上解决完整的表型 通过以下游分子通路为靶点来研究这种疾病的光谱。理想情况下，PTHS将在其 根，通过增加完整的TCF4基因拷贝的表达来使基因表达水平正常化。我们 假设小分子能够在出生后早期上调TCF4的表达 发育，也许是成年，会纠正PTHS的表型。开发一种知情的治疗方法 干预策略和为最终的临床试验确定TCF4激活剂，我们将完成三个目标：(1) 建立TCF4的生物分布以指导治疗提供，(2)评估早期或早期的表型救援 迟发的TCF4正常化，以及(3)确定提高TCF4水平的方法。我们已经开发出 和经过验证的强大工具，以促进这些目标中的每一个，这对指导临床 PTHS遗传正常化治疗的进展。

PROJECT SUMMARY 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.