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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：
10549344
负责人：
BRUCE D GELB
金额：
$ 86.07万
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：
2017-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549344
关键词：
ADME Study Acceleration Address Adopted Adult Animals Biological 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 Premature Mortality RAF1 gene Research Personnel Robotics Signal Transduction System Technology Testing Therapeutic Toxic effect Veins Vial device Wing accurate diagnosis causal variant comorbidity disease-causing mutation drug development efficacy evaluation fly gene discovery high throughput screening improved induced pluripotent stem cell interest mouse model mutant novel therapeutics prognostication screening side effect small molecule small molecule libraries stem cell model 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.

儿童心血管疾病，包括先天性心脏缺陷（CHD）和心肌和

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy.

DOI：
10.1016/j.isci.2021.102306
发表时间：
2021-04-23
期刊：
iScience
影响因子：
5.8
作者：
Das TK;Gatto J;Mirmira R;Hourizadeh E;Kaufman D;Gelb BD;Cagan R
通讯作者：
Cagan R

Feeder-free generation and characterization of endocardial and cardiac valve cells from human pluripotent stem cells.

DOI：
10.1016/j.isci.2023.108599
发表时间：
2024-01-19
期刊：
ISCIENCE
影响因子：
5.8
作者：
Liu, Clifford Z.;Prasad, Aditi;Jadhav, Bharati;Liu, Yu;Gu, Mingxia;Sharp, Andrew J.;Gelb, Bruce D.
通讯作者：
Gelb, Bruce D.

Burden of Cardiomyopathic Genetic Variation in Lethal Pediatric Myocarditis.

DOI：
10.1161/circgen.121.003426
发表时间：
2021-08
期刊：
Circulation. Genomic and precision medicine
影响因子：
0
作者：
Kontorovich AR;Tang Y;Patel N;Georgievskaya Z;Shadrina M;Williams N;Moscati A;Peter I;Itan Y;Sampson B;Gelb BD
通讯作者：
Gelb BD

A de novo pathogenic BMP2 variant-related phenotype with the novel finding of bicuspid aortic valve.

DOI：
10.1002/ajmg.a.61992
发表时间：
2021-03
期刊：
American journal of medical genetics. Part A
影响因子：
0
作者：
Ahluwalia N;Gelb BD
通讯作者：
Gelb BD

Myopathic Cardiac Genotypes Increase Risk for Myocarditis.

DOI：
10.1016/j.jacbts.2021.06.001
发表时间：
2021-07
期刊：
JACC. Basic to translational science
影响因子：
0
作者：
Kontorovich AR;Patel N;Moscati A;Richter F;Peter I;Purevjav E;Selejan SR;Kindermann I;Towbin JA;Bohm M;Klingel K;Gelb BD
通讯作者：
Gelb BD