High-Throughput Screening for Novel Drug Discovery Using Patient-Specific Induced Pluripotent Stem Cells for Familial Hypertrophic Cardiomyopathy
Abstract
Topic Area: Cardiomyopathy. Familial hypertrophic cardiomyopathy (HCM) is the most common heritable heart disease in the world, affecting about 1 out of 500 people. It is characterized by a thickening of the heart tissue, which leads to a reduced volume in the heart chamber cavities, impaired relaxation time, arrhythmias, and ultimately sudden cardiac death (SCD). Progression of the symptoms of HCM is further exacerbated by intense physical activity. Because military Service men and women maintain a very stressful physical training period and lifestyle, the chances of Service members developing and exacerbating clinical manifestations of this disease are significantly increased. This heritable form of HCM has been reported as one of the most common causes of SCD associated with physical exertion by young athletes and the US military. In spite of significant progress in the HCM field, therapeutic options to cure this disease are still lacking. Although beta-adrenergic and calcium channel blockers treatments show some beneficial effects, these drugs fail to prevent the progression of disease, and patients will develop heart failure eventually. The unlimited availability of iPSC-CMs derived from patients with HCM enables robust high-throughput screening for novel and efficacious medicine for treating and saving millions of HCM patients world-wide. The Principal Investigator will screen for novel small molecules to rescue cell area (a well-known HCM marker) of HCM-iPSC-CMs using a chemically diverse library of 26,000 small molecules, which contains Food and Drug Administration-approved drugs as well as novel drug-like compounds. These initial compounds will be tested in (1) multiple hiPSC lines with other HCM mutations and (2) hiPSC-based engineered heart tissue (EHT). In this way, we will be able to more thoroughly test effects of candidate drugs at the tissue level and under different genetic backgrounds, similar to what would be seen in the clinical environment. Finally, the effect of our top three candidate drugs will be investigated through transcriptome profiling of genes associated with varied HCM phenotypes such as calcium handling, hypertrophy, and fibrosis. This proposal will be a great aid in the discovery of novel and efficacious drugs for HCM patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010036
Entities
People
- Jin‐Kyu Park
Organizations
- United States Army
- Yale University