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Bioengineering Mature Human Pluripotent Stem Cell-Derived Cardiomyocytes for Predictive Drug-Induced Toxicity Testing

Award Number: R44HL149566
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Bioengineering Mature Human Pluripotent Stem Cell-Derived Cardiomyocytes for Predictive Drug-Induced Toxicity Testing - PROJECT SUMMARY Nearly 90% of drugs under development fail to reach the market. Many of these failures occur due to cardiotoxicity, usually when the candidate molecule induces cardiac arrhythmias. In a few notable cases, some drugs pass pre-clinical screens and clinical trials, only to be removed from the market once toxic effects are discovered in large patient populations. These failures represent a tremendous source of waste and constitute a significant part of the ~$2 billion cost of bringing a single drug to market. Consequently, the FDA now mandates that all drugs undergo in vitro cardiotoxicity testing before being tested in humans. This has led to a significant and growing market for tools and technologies that enable earlier detection of toxic effects before exposure to patients. However, current screening methods fall short of predicting how a drug will behave in the body; indeed there is a pressing need for more predictive model systems. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are an attractive model for in vitro preclinical toxicity screening; they are relatively easy to maintain, are derived from human tissue, and have the potential to reduce the need for animal experimentation. However, at present, iPSC-CM based assays do not properly replicate the function of the human heart. These cells exhibit phenotypes similar to that of fetal tissue and do not respond as expected to drugs of known effect; in some cases, known bad-actor drugs fail to induce arrhythmias, while others only show in vivo cardiotoxicity when exposed to supra-physiological doses of the drug in question. The drug discovery industry and its regulators realize the potential of iPSC-CMs for early cardiotoxicity screening, but also understand that—at present—there are significant limitations to their use in the drug development process. Thus, it is clear that the production of mature cardiac tissues that accurately recapitulate in vivo drug responses represents a significant opportunity for reducing cost and waste in drug development. NanoSurface Biomedical, Inc., aims to develop an enhanced iPSC-CM cell line that has been optimized for highly predictive drug-induced cardiotoxicity screening. We hypothesize that iPSC-CMs that give more predictive results in in vitro cardiotoxicity detection can be made by combining nanoscale extracellular cues with biochemical and molecular biological stimuli that drive their maturation. We will first focus on demonstrating that these enhanced iPSC-CMs can correctly classify drugs that are currently improperly screened (Phase 1, Aim 1). After validation, we will generate a stable cell line that encompasses the maturation factors determined in Phase 1 in preparation for scaling and commercial production (Phase 2, Aim 1). Commercialization efforts will further be facilitated by characterizing transcriptomic, structural, and functional phenotypes of the predictive cell line and in identifying a set of key physiological metrics that will be used for in-line quality control (Phase 2, Aim 2). Last, we will validate and generate data for market release with our research partners in the drug development industry and regulatory bodies (Phase 2, Aim 3).


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: 2024 ( Subtotal = $0 )
2024	2021	CURI BIO INC	3000 WESTERN AVE	SEATTLE	WA	98121	KING	USA	Cardiovascular Diseases Research	000	3	1/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $993,756 )
2021	2021	CURI BIO, INC.	3000 WESTERN AVE	SEATTLE	WA	98121	KING	USA	Cardiovascular Diseases Research	002	3	7/27/2021	NON-COMPETING CONTINUATION	$745,488
2021	2021	CURI BIO, INC.	3000 WESTERN AVE	SEATTLE	WA	98121	KING	USA	Cardiovascular Diseases Research	003	3	7/28/2021	SUPPLEMENT FOR EXPANSION	$179,200
2021	2021	CURI BIO, INC.	3000 WESTERN AVE	SEATTLE	WA	98121	KING	USA	Cardiovascular Diseases Research	001	2	3/19/2021	SUPPLEMENT FOR EXPANSION	$69,068
2021	2019	CURI BIO, INC.	3000 WESTERN AVE	SEATTLE	WA	98121	KING	USA	Cardiovascular Diseases Research	000	1	2/23/2021	NEW	$0
														Subtotal = $993,756

Issue Date FY: 2020 ( Subtotal = $750,000 )
2020	2020	NANOSURFACE BIOMEDICAL, INC.	4000 MASON RD STE 304	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	2	6/5/2020	EXTENSION WITH OR WITHOUT FUNDS	$750,000
														Subtotal = $750,000

Issue Date FY: 2019 ( Subtotal = $225,000 )
2019	2019	NANOSURFACE BIOMEDICAL, INC.	4000 MASON RD STE 304	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	1	8/16/2019	NEW	$225,000
														Subtotal = $225,000

Grand Total All Awards = $1,968,756

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Bioengineering Mature Human Pluripotent Stem Cell-Derived Cardiomyocytes for Predictive Drug-Induced Toxicity Testing

Award Number: R44HL149566

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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