TCF4 in Pitt-Hopkins syndrome

皮特-霍普金斯综合征中的 TCF4

• 批准号: 10459528
• 负责人: BENJAMIN D PHILPOT
• 金额: $ 33.73万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459528
• 关键词: Address; Adolescent; Adult; Age; Alleles; Anatomy; Biodistribution; Brain; Clinical Trials; Development; Disease; Electroencephalography; Electrophysiology (science); Embryo; Exhibits; Fibroblasts; Fluorescence; Future; Gene Expression; Genes; Genetic; Human; Hyperactivity; Intellectual functioning disability; Intervention; Knowledge; Modeling; Molecular; Mus; Mutation; Neonatal; Neurodevelopmental Disorder; Neurons; Pathogenicity; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Pitt-Hopkins syndrome; Plant Roots; Preclinical Testing; Reporter; Research; Seizures; Speech; Symptoms; TCF7L2 gene; Therapeutic; Therapeutic Intervention; Treatment Efficacy; autism spectrum disorder; behavioral phenotyping; cell type; clinical development; comorbidity; genetic approach; motor impairment; mouse model; nanoluciferase; neonate; neurodevelopment; novel; novel therapeutics; postnatal; postnatal development; preclinical study; screening; severe intellectual disability; small molecule; tool; transcription factor

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.

项目概要 皮特霍普金斯综合征 (PTHS) 是一种神经发育障碍，其特征是言语丧失、脑电图检查 异常、癫痫、运动障碍和严重智力障碍。不幸的是，没有 针对其核心症状的治疗。 PTHS 是由 TCF4 的单倍体不足引起的，TCF4 是一种转录因子， 调节数百个基因，使得几乎不可能治疗性地解决完整的表型 通过靶向下游分子途径来了解疾病谱。理想情况下，PTHS 将在其正常情况下接受治疗 通过增强完整 TCF4 基因拷贝的表达来使基因表达水平正常化。我们 假设小分子能够在产后早期上调 TCF4 表达 发育，或许到成年，将纠正 PTHS 表型。开发一种知情的治疗方法 干预策略并确定最终临床试验的 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实施，(2) 评估早期或早期的表型救援 TCF4 的迟发正常化，以及 (3) 确定提高 TCF4 水平的方法。我们开发了 并验证了强大的工具来促进每个目标，这些目标对于指导临床是不可或缺的 开发 PTHS 基因正常化治疗方法。