Pediatric Heart Disease: Getting from Mutations to Therapeutics

小儿心脏病：从突变到治疗

基本信息

批准号：
9440083
负责人：
BRUCE D GELB
金额：
$ 1.93万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-28 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9440083
关键词：
ADME Study Address Adopted Adult Adverse effects Animals Back Biological Biological Models Cardiac Cardiovascular Diseases Caring Cell Line Cell model Cells Chemicals Childhood Clinical Trials Design Comorbidity Complex Congenital Heart Defects Data Development Disease Disease model Drosophila genus Drosophila melanogaster Drug Interactions Drug usage Eye FDA approved Genetic Genomics Heart Diseases Heart Hypertrophy Hereditary Disease 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 disease-causing mutation drug development fly gene discovery high throughput screening improved induced pluripotent stem cell interest mouse model mutant novel therapeutics prognostic screening small molecule small molecule libraries trait

项目摘要

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.

小儿心血管疾病，包括先天性心脏病 (CHD) 和心肌和由于心脏并发症和过早死亡，传导系统疾病仍然极具挑战性。由于大多数这些疾病都是遗传性的，过去 30 年的努力重点是确定其病因突变。特别是对于孟德尔特征，例如努南综合征和相关疾病（ RASopathies），这非常成功。更新的基因组技术加速了基因发现用于儿科心血管疾病，包括遗传复杂的疾病。这些基因发现是通过更准确的诊断、更好的预测和改进临床试验设计来改善护理。除了极少数例外，基于新疗法的新疗法的开发并不少见。这些基因的发现使我们能够了解疾病的发病机制。寻找治疗方法小儿心血管疾病将具有挑战性，因为生物靶标通常是细胞的核心体内平衡（例如 RAS/MAP 激酶信号传导），因此不能在不使用药物的情况下长期完全抑制产生的副作用超过其益处。对于这个 R35 机制，我和我的杰出合作者具有相关专业知识的研究人员打算利用药物开发管道来解决这一差距，该管道开始通过高通量筛选克服果蝇疾病模型中的蛹致死率使用 96 孔板和机器人技术覆盖可药物空间 (n=14,400) 的化学库。放映于整个动物的执行是不可知的，并且具有提供同步读出的假定优势功效和毒性。我们提供的初步数据表明我们已经使用苍蝇实现了这一目标努南综合征合并肥厚性心肌病的 RAF1 突变模型。果蝇的后续步骤包括确认小瓶中的初始命中，确定对成蝇表型（例如粗糙眼）的功效，异位翼静脉和心脏肥大。候选化合物的备份库，通常为 60-80 个化学邻居将被挑选出具有最理想药物特性的化学邻居，然后在果蝇模型中进行筛选。使用一组明确的果蝇缺陷品系，将建立目标和反目标，以进一步实现一轮理性药理学。 ADME 研究将用于减少药物间相互作用的可能性。在与此同时，我们将利用果蝇模型进行文库筛选，以寻求 FDA 批准的药物的重新利用，系统药物基因组学。然后将针对人类表型测试主要化合物和药物诱导具有致病突变的多能干细胞系以提高疗效。最有前途的药物然后将使用适当的终点在现有小鼠模型（例如 Raf1 突变小鼠的 HCM）中进行测试。总的来说，所提出的方法将显着促进新疗法的识别儿科心血管疾病，首先是 RASopathies，后来是其他特征。如果稳健的话，这将为 NHLBI 感兴趣的其他遗传性状提供了一个范例。