TCF4 in Pitt-Hopkins syndrome

项目摘要 Pitt-Hopkins综合征（PTHS）是一种神经发育障碍性疾病， 异常、癫痫、运动障碍和严重智力残疾。不幸的是， 治疗其核心症状。PTHS是由TCF 4的单倍不足引起的，TCF 4是一种转录因子， 调节数百个基因，使得几乎不可能在治疗上解决整个表型 通过靶向下游分子通路来治疗疾病谱。理想情况下，PTHS将在其 根，通过增加完整的TCF 4基因拷贝的表达，使基因表达水平正常化。我们 假设能够在出生后早期上调TCF 4表达小分子 发育，也许进入成年，将纠正PTHS表型。开发一种知情的治疗方法 为了制定干预策略并为最终的临床试验识别TCF 4激活剂，我们将完成三个目标：（1） 建立TCF 4的生物分布以指导治疗，（2）评估早期或晚期TCF的表型挽救， TCF 4迟发性正常化，以及（3）确定增加TCF 4水平的方法。我们已经开发 并验证了强大的工具，以促进每一个这些目标，这是不可或缺的指导临床 PTHS的遗传正常化治疗的发展。

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.