Funding opportunities

Funding Type: 
Early Translational IV
Grant Number: 
Principle Investigator: 
Funds requested: 
$6 361 618
Funding Recommendations: 
Grant approved: 
Public Abstract: 

This project uses patient hiPSC-derived cardiomyocytes to develop a safe and effective drug to treat a serious heart health condition. This research and product development will provide a novel method for a human genetic heart disorder characterized by long delay (long Q-T interval) between heart beats caused by mutations in the Na+ channel α subunit. Certain patients are genetically predisposed to a potentially fatal arrhythmogenic response to existing drugs to treat LQT3 since the drugs have off-target effects on other important ion channels in cardiomyocytes. We will use patient-derived hiPSC-cardiomyocytes to develop a safer drug (development candidate, DC) that will retain efficacy against the "leaky" Na+-channel yet minimize off-target effects in particular against the K+ hERG channel that can be responsible for the existing drug’s pro-arrhythmic effect. Since this problem is thought to occur severely in patients with the common KCHN2 variant, K897T (~33% of the white population), removing the off-target liability addresses a serious unmet clinical need. Futher, since we propose to modify an existing drug (i.e., do drug rescue), the path from patient-specific hiPSCs to clinic might be easier than for a completely new chemical entity. Lastly, an appealing aspect is that the hiPSCs were derived from a child to test his therapy, & we aim to produce a better drug for his treatment. Our goal is to complete development of the DC and initiate IND-enabling in vivo studies.

Statement of Benefit to California: 

In the US, an estimated 850,000 adults are hospitalized for arrhythmias each year, making arrhythmias one of the top five causes of healthcare expenditures in the US with a direct cost of more than $40 billion annually for diagnosis, treatment & rehabilitation. The State of California has approximately 12% of the US population which translates to 102,000 individuals hospitalized every year for arrhythmias. Another 30,000 Californians die of sudden arrhythmic death syndrome every year. Arrhythmias are very common in older adults and because the population of California is aging, research to address this issue is important for human health and the State economy. Most serious arrhythmias affect people older than 60. This is because older adults are more likely to have heart disease & other health problems that can lead to arrhythmias. Older adults also tend to be more sensitive to the side effects of medicines, some of which can cause arrhythmias. Some medicines used to treat arrhythmias can even cause arrhythmias as a side effect. In the US, atrial fibrillation (a common type of arrhythmia that can cause problems) affects millions of people & the number is rising. Accordingly, the same problem is present in California. Thus, successful completion of this work will not only provide citizens of California much needed advances in cardiovascular health technology & improvement in health care but an improved heart drug. This will provide high paying jobs & significant tax revenue.

Review Summary: 

The goal of this Development Candidate proposal is to identify and develop a safer version of a drug commonly used to treat a human genetic heart disorder, Long QT Syndrome 3 or LQT3. Certain LQT3 patients are genetically predisposed to a potentially fatal arrhythmogenic response to the drugs used to treat their disease. This predisposition is a result of the drug having an off-target effect on a cardiomyocyte potassium channel in addition to the intended effect on a sodium channel. The applicants propose to use patient iPSC-derived cardiomyocytes to screen 63 analogs of the marketed drug to identify variant(s) that retain potency against the sodium channel but no longer inhibit the potassium channel. Candidate compounds will be subjected to in vitro pharmacology and toxicology assays as well as in vivo bioavailability and safety studies before selecting a development candidate.

Objective and Milestones
- The Target Product Profile is reasonable and clear and the milestones are straightforward with clear Go/No-Go decisions.

Rationale and Significance
- The drug being optimized in this protocol exacerbates arrhythmias in about 10% of patients due to off target effects. There are no anti-arrhythmic drugs on the market with clean target specificity.

- The use of human stem cell-derived cardiomyocytes is well justified, as this is the only way to obtain the cells needed for the proposed screen.

Feasibility and Design
- The preliminary data show that iPSC can be used to make cardiomyocytes with long QT phenotypes.

- Preliminary data support the idea that a kinetic imaging cytometer will be useful for assessing off-target effects.

- It was not completely clear that the sub-contractor would be able to make the patient iPSC-derived cardiomyocytes with consistent maturity.

- There was some concern that no in vivo efficacy tests were included to support nomination of a development candidate.

Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team
- The PI has a strong track record in medicinal chemistry.

Collaborations, Assets, Resources and Environment
- The collaboration between the chemistry team and the biologists and electrophysiologists is logical. It is valuable to have an ion channel expert on the team.

Responsiveness to the RFA
- This proposal is responsive to the RFA since iPSC-derived cells are required for the proposed screens.