Funding opportunities

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

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06410
Funds requested: 
$2 924 284
Funding Recommendations: 
Not recommended
Grant approved: 
No
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.
Review Summary: 
Executive Summary Long QT syndrome (LQT) is a cardiac electrical dysfunction that can lead to sudden cardiac death (SCD). This condition can be either genetic or can arise as a side effect of certain drugs. SCD is common cause for the withdrawal of drugs that are either in development or already approved. The applicant proposes to utilize reprogramming technology to generate induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) from patients with dysfunction representing a wide spectrum of LQT disorders. These cells will be incorporated into a high throughput assay to detect a range of drug induced LQTs. Secondly, the applicants plan to chemically modify existing approved LQT inducing drugs and use this screening tool to identify compounds where this adverse effect has been successfully removed. Lastly, they will use this assay platform to look for novel drugs to treat LQT. Research Plan - While reviewers agreed that LQT is a significant clinical problem, the proposed approach is not novel. In fact, hiPSC-CM are already in use by industry to detect drug induced LQT and similar approaches have already been published by others in high impact journals. - The project is more focused on technology development rather than on work aimed at characterizing or testing a possible therapeutic candidate. - Reviewers were not enthusiastic about the aim to chemically modify already approved drugs to improve the safety profile, which is very challenging to do while preserving the therapeutic activity. This is a more suitable activity for a pharmaceutical company rather than an academic research program. Principal Investigator - Reviewers expressed concern regarding the PI’s recent productivity and highlighted his/her very limited number of senior author publications, despite a successful record securing funding. - The PI has assembled a strong team of collaborators that raise the feasibility of completing the proposed studies. However, the PI’s lack of a documented track record in the field dampened reviewer enthusiasm for investing in the proposal. - Career development plan is well defined with strong mentors. Institutional Commitment - The institution has demonstrated a strong commitment to the investigator. Responsiveness - The proposal was viewed as broadly responsive to the RFA.
Conflicts: 
  • Sean Palecek

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