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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 Number: R42HL158510
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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 - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2021	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	3/14/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,407,473 )
2024	2024	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	005	3	8/12/2024	SUPPLEMENT FOR EXPANSION	$13,554
2024	2024	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	006	3	8/15/2024	SUPPLEMENT FOR EXPANSION	$152,796
2024	2024	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	003	3	8/7/2024	NON-COMPETING CONTINUATION	$920,237
2024	2024	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	001	2	6/12/2024	SUPPLEMENT FOR EXPANSION	$16,853
2024	2024	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	000	2	1/22/2024	SUPPLEMENT FOR EXPANSION	$120,499
2024	2024	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	002	2	6/27/2024	SUPPLEMENT FOR EXPANSION	$9,527
2024	2024	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	004	3	8/9/2024	SUPPLEMENT FOR EXPANSION	$174,007
														Subtotal = $1,407,473

Issue Date FY: 2023 ( Subtotal = $1,056,800 )
2023	2023	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	001	2	8/3/2023	EXTENSION WITH OR WITHOUT FUNDS	$1,056,800
2023	2021	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	3/6/2023	NEW	$0
														Subtotal = $1,056,800

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	8/22/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $299,871 )
2021	2021	VALA SCIENCES INC.	6370 NANCY RIDGE DR STE 106	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	5/26/2021	NEW	$299,871
														Subtotal = $299,871

Grand Total All Awards = $2,764,144

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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 Number: R42HL158510

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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