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Combined Cardiomyopathy, e.g., of Cancer Chemotherapeutics, and Proarrhythmia for Cardiotoxicity Clinical Trials-in-a-Dish (CTiD) with iPSC-Derived Cardiomyocytes

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 4R42HL158510-02
Agency Tracking Number: R42HL158510
Amount: $1,056,800.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NHLBI
Solicitation Number: PA20-265
Solicitation Year: 2020
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-08-03
Award End Date (Contract End Date): 2025-07-31
Small Business Information
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United States
DUNS: 612181532
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Socially and Economically Disadvantaged: No
Principal Investigator
 (858) 461-6861
Business Contact
Phone: (858) 461-6861
Research Institution
STANFORD, CA 94305-2004
United States

 Nonprofit College or University

Cardiotoxicity is a leading cause of drug discovery attrition across all of preclinical and clinical drug discovery.
While the FDA and the Comprehensive in vitro Proarrhythmia Assay initiative (CiPA) are focused primarily on
predicting proarrhythmic effects, drug attrition due to cardiomyopathy, or primary cardiac cytotoxicity, may be
even more prevalent, is typically currently only carried out via animal studies, and limits dosage for many
cancer chemotherapeutics. Due to improving cancer survival, it is increasing common for more cancer
survivors of some cancer types to die of cardiac diseases due to cancer treatment side effects than cancer
recurrence. Cardiac contractions are initiated by electrical depolarizations (action potentials, APs) that
propagate through the heart and initiate calcium (Ca2+) transients that activate the contractile apparatus.
Importantly, dysregulation of Ca2+ can trigger inappropriate early-after- and delayed-after- depolarizations
(EADs and DADs) that initiate arrhythmias, inhibit mitochondrial function, and pathologically alter expression of
contractile proteins. Chemotherapy and other drugs can also directly impair mitochondrial function, which is
primarily thought to cause cytotoxicity, but can also cause arrhythmias. Cardiomyocytes are also
heterogeneous in their voltage, calcium, and contractile functions, and in their responses to therapeutic
candidates. Thus, it is highly desirable to simultaneously measure AP, Ca2+ and contractile function on a cell-
by-cell basis, in human cardiomyocytes, but this is not possible with current test methods. To address this
unmet need we propose to develop a high throughput (robotic) Kinetic Image Cytometry that simultaneously
quantifes voltage, calcium, and contractile motion in cardiomyocytes derived from human induced pluripotent
stem cells (hiPSC-CMs). The hiPSC-CMs will be labeled with fluorescent indicators of calcium and voltage,
and the cells imaged via high-speed automated microscopy during contractile activity. The use of hiPSC-CMs
will enable “clinical trials” in a dish, in which test compounds are tested across cells representing several
donors. Phase I of this Fast-Track STTR project will develop the basic protocol and perform a proof-of-concept
screen of 30 test compounds on hiPSC-CMs representing 5 donors. In Phase II, a large validation study (~350
compounds, 7-concentration dose-response, 30 min and 72 hr exposures) will be performed. Artificial
intelligence will be utilized to optimize the sensitivity and specificity of the assay by detecting complex
arrhythmia waveforms. This assay represents a human-based preclinical model that will be less expensive
and more predictive for cardiotoxicity testing than animal models and will be marketed to the pharmaceutical
industry for contract research.

* Information listed above is at the time of submission. *

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