Therapeutic Intervention and Prevention of Long QT Syndrome/Cardiac Repolarization-Mediated Sudden Cardiac Death

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06410
Investigator: 
ICOC Funds Committed: 
$0
oldStatus: 
Closed
Public Abstract: 
Sudden cardiac death (SCD) due to the inability for the heart to electrically reset properly after the heart contracts is a major contributor towards overall cardiovascular mortality, the leading cause of death in the US and world. This cardiac electrical defect, otherwise known as long QT syndrome (LQT), results from drugs or genetic differences that may perturb the cardiac electrical channels of the heart. As a result, SCD due to drugs causing LQTs has become the most common reason the FDA requests withdrawal of previously approved or developing drugs. Though drugs are currently tested for their ability to cause LQT using heterologous animal cell culture systems, these systems do not recapitulate the milieu of human cardiac cells, thus leading to imprecise drug toxicity evaluation for LQT. However, cellular reprogramming of cells (induced pluripotent stem cells) from patients with acquired or inherited LQT now provides an innovative approach towards obtaining human cardiac cells that may be used to not only accurately screen all drugs for their ability to cause LQT, but also identify new compounds that may treat this disorder. To this end, we propose to create a high-throughput cardiac electrical assay for rapid screening of drugs on a panel of human cardiomyocytes derived from reprogrammed cells of patients that represent a wide spectrum of LQT disorders. These assays will provide a novel and more accurate approach towards preventing as well as treating SCD in the future.
Statement of Benefit to California: 
Sudden cardiac death (SCD) due to the inability for the heart to electrically reset properly after the heart contracts is a major contributor towards overall cardiovascular mortality, the leading cause of death in California and the US. This cardiac electrical defect, otherwise known as long QT syndrome (LQT), results from drugs or genetic differences that may perturb the cardiac electrical channels of the heart. As a result, SCD due to drugs causing LQT has become the most common reason the FDA requests withdrawal of previously approved or developing drugs. Thus, developing rapid assays that reliably screen drugs for their ability to cause or treat LQT in human cardiac cells would not only prevent drug-induced SCD, but also treat patients who are genetically susceptible to SCD. To this end, we propose to create a high-throughput cardiac electrical assay for rapid screening of drugs on a panel of human cardiomyocytes derived from reprogrammed cells of patients that represent a wide spectrum of LQT disorders. This innovative assay may directly help California’s biotechnology companies to rapidly and more accurately test the LQT toxicity profile of newly developing drugs prior to clinical trials as well as create a high-content platform to identify new compounds that may treat SCD. Overall, the proposed studies will provide a novel and more precise strategy towards preventing as well as treating SCD in State of California.

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