Pediatric Heart Disease: Getting from Mutations to Therapeutics

小儿心脏病：从突变到治疗

• 批准号: 10112285
• 负责人: BRUCE D GELB
• 金额: $ 86.08万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112285
• 关键词: ADME Study; Address; Adopted; Adult; Animals; Back; Biological; Biological Models; Cardiac; Cardiovascular Diseases; Caring; Cell Line; Cells; Chemicals; Childhood; Clinical Trials Design; Complex; Congenital Heart Defects; Data; Development; Disease; Disease model; Drosophila genus; Drosophila melanogaster; Drug Interactions; Drug usage; Eye; FDA approved; Genetic; Genetic Diseases; Genomics; Heart Diseases; Heart Hypertrophy; Homeostasis; Human; Hypertrophic Cardiomyopathy; Libraries; Methods; Mission; Mitogen-Activated Protein Kinases; Modeling; Mutant Strains Mice; Mutation; Myocardial; National Heart, Lung, and Blood Institute; Noonan Syndrome; Other Genetics; Pathogenesis; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Phenotype; Plant Roots; Premature Mortality; Pupa; RAF1 gene; Research Personnel; Robotics; Signal Transduction; System; Technology; Testing; Therapeutic; Toxic effect; Veins; Vial device; Wing; accurate diagnosis; base; causal variant; comorbidity; disease-causing mutation; drug development; fly; gene discovery; high throughput screening; improved; induced pluripotent stem cell; interest; mouse model; mutant; novel therapeutics; prognostic; screening; side effect; small molecule; small molecule libraries; stem cell model; trait

Pediatric cardiovascular disorders, which comprise congenital heart defects (CHD) and myocardial and conduction system diseases, remain highly challenging due to cardiac co-morbidities and premature mortality. As most of these disorders are genetic, efforts over the past 30 years have focused on identifying their causal mutations. Particularly for Mendelian traits such as Noonan syndrome and related disorders (the RASopathies), this has been highly successful. Newer genomic technologies have accelerated gene discovery for pediatric cardiovascular disorders, including genetically complex ones. These genetic discoveries are improving care through more accurate diagnosis, better prognostication, and refinement of clinical trial design. What has not occurred with rare exception is the development of novel therapies based on the new understanding of disease pathogenesis enabled by these gene discoveries. Finding therapies for pediatric cardiovascular disorders will be challenging because the biological targets are generally central to cell homeostasis (e.g., RAS/MAP kinase signaling) so cannot be completely inhibited for long periods without incurring side effects that would outweigh their benefits. For this R35 mechanism, I and my outstanding co- investigators with relevant expertise intend to address this gap using a drug development pipeline that begins with high-throughput screening to overcome pupal lethality in Drosophila melanogaster models of disease with a chemical library that covers druggable space (n=14,400) using 96-well plates and robotics. Screening in whole animals is performed agnostically and has the putative advantage of providing a simultaneous read out of efficacy and toxicity. We provide preliminary data showing that we have already achieved this using a fly RAF1 mutant model of Noonan syndrome with hypertrophic cardiomyopathy. Subsequent steps with fruit flies include confirmation of initial hits in vials, determining efficacy against adult fly phenotypes such as rough eye, ectopic wing veins and heart hypertrophy. Back-up libraries for the candidate compounds, typically 60-80 chemical neighbors, will be culled for ones with most desirable drug traits and then screened in the fly models. Using a defined set of fruit fly deficiency lines, targets and anti-targets will be established to enable further rounds of rational pharmacology. ADME studies will be used to reduce potential for drug-drug interactions. In parallel, we will pursue repurposing of FDA-approved drugs using library screening with fruit fly models and systems pharmacogenomics. Leading compounds and drugs will then be tested against phenotypes in human induced pluripotent stem cell lines with the disease-causing mutation for efficacy. The most promising drugs will then be tested in existing mouse models (e.g., HCM in Raf1 mutant mice) using appropriate endpoints. Taken as a whole, the approach proposed will significantly advance the identification of novel therapeutics for pediatric cardiovascular diseases, starting with the RASopathies and later for other traits. If robust, this will provide a paradigm that can be adopted for other genetic traits of interest to the NHLBI.

儿童心血管疾病，包括先天性心脏病(CHD)和心肌梗死 由于心脏并发症和过早死亡，传导系统疾病仍然具有极大的挑战性。 由于这些疾病大多是遗传性的，过去30年来的努力主要集中在确定其原因上。 突变。尤其是孟德尔特征，如努南综合征和相关疾病( Rasopathies)，这是非常成功的。更新的基因组技术加速了基因发现 用于儿科心血管疾病，包括基因复杂的疾病。这些基因发现是 通过更准确的诊断、更好的预测和临床试验设计的改进来改善护理。 没有罕见的例外是基于新的治疗方法的新疗法的发展 这些基因的发现使人们能够理解疾病的发病机制。寻找治疗方法 儿科心血管疾病将是具有挑战性的，因为生物靶点通常是细胞的中枢 因此，动态平衡(如RAS/MAP激酶信号)不能长期完全被抑制 招致的副作用将超过它们的好处。对于这个R35机制，我和我杰出的合作伙伴- 具有相关专业知识的调查人员打算利用一条药物开发管道来填补这一缺口，该管道始于 用高通量筛查克服果蝇黑腹果蝇疾病模型中的蛹致死性 一个化学图书馆，覆盖了可用药空间(n=14,400)，使用96孔板和机器人。筛选入 整个动物的行为是不可知的，并具有提供同时读出的假定优势 药效和毒性。我们提供的初步数据表明，我们已经使用苍蝇实现了这一点 Noonan综合征合并肥厚型心肌病RAF1突变模型的建立。后续步骤与果蝇 包括确认瓶子中初始命中，确定对诸如粗糙眼等成虫苍蝇表型的疗效， 异位翼状静脉和心脏肥大。候选化合物的备份库，通常为60-80 化学邻居，将被挑选出具有最令人满意的药物特征的，然后在苍蝇模型中进行筛选。 利用一套已定义的果蝇缺陷系，将建立目标和反目标，以使进一步 理性药理学的轮回。ADME研究将用于减少药物-药物相互作用的可能性。在……里面 同时，我们将利用果蝇模型和文库筛选来实现FDA批准的药物的再利用 系统药物基因组学。然后，主要化合物和药物将针对人类的表型进行测试 诱导具有致病突变作用的多能干细胞系。最有前途的药物 然后将在现有的小鼠模型(例如，Raf1突变小鼠的HCM)中使用适当的终点进行测试。 总体而言，所提出的方法将极大地促进对 儿科心血管疾病，从Rasopathies开始，后来是其他特征。如果稳健，这将是 提供了一个范例，可用于NHLBI感兴趣的其他遗传性状。