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High-throughput, all-optical assay in human cardiomyoctes for clinically relevant prediction of drug induced cardiotoxity.

Award Number: R44HL126314
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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High-throughput, all-optical assay in human cardiomyoctes for clinically relevant prediction of drug induced cardiotoxity. - ¿ DESCRIPTION (provided by applicant): Toxicity accounts for approximately 20% of drug attrition, of which nearly one third is attributed to cardiovascular issues, in particular arrhythmias.1 The cost of bringing a new drug to market can exceed $1.2 billion and require more than 10 years of research. Thus, it is critical to identify cardiotoxicity early in developmen. Current in vitro screening assays for pro--arrhythmic drug effects focus on measuring inhibition of the hERG potassium channel, which has been linked to potentially lethal Torsades de Pointes arrhythmias (TdP).2 The hERG assay, however, lacks high sensitivity and specificity: not all QT prolongation is due to block of hERG alone and not all hERG blockers result in QT prolongation or induce TdP. To address these limitations, regulatory bodies have created the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative2, which proposes use of cardiomyocytes derived from human stem cells as an in vitro model for arrhythmogenic drug potential. Establishment of this model for toxicity screening requires detailed characterization of the cardiomyocyte action potential (AP) and calcium transient (CT), the response of APs/CTs to drugs, and the correlation to clinical outcomes in humans. High--throughput tools needed for performing these measurements, however, have been lacking. Here we propose to develop a high--throughput, all--optical electrophysiology platform for cardiotoxicity screening in sem cell--derived cardiomyocytes. With our Phase I award, we demonstrated that the Optopatch platform could be used to detect changes in the electrophysiological characteristics of human derived CMs following both acute and chronic drug treatment, albeit with the throughput of a single well per recording. To highly parallelize these measurements, we propose building a 96--well plate Optopatch instrument for simultaneous recording of voltage and calcium waveforms under paced conditions from 24 wells. This geometry will provide nearly two orders of magnitude improvement in throughput of our assay. Optopatch constructs will be optimized to allow for incorporation of the actuator and reporter proteins in each cell. We will utilize this platform to screen 50 compounds with known risk scores for Torsades de Pointes in different sources of human cardiomyocytes and use this data to develop a predictive algorithm of arrhythmogenicity.


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: 2022 ( Subtotal = $5 )
2022	2017	Q-STATE BIOSCIENCES	179 SIDNEY ST	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cardiovascular Diseases Research	000	3	9/26/2022	NON-COMPETING CONTINUATION	$5
														Subtotal = $5

Issue Date FY: 2019 ( Subtotal = -$5 )
2019	2017	Q-STATE BIOSCIENCES, INC.	179 SIDNEY ST	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cardiovascular Diseases Research	000	3	7/29/2019	NON-COMPETING CONTINUATION	-$5
														Subtotal = -$5

Issue Date FY: 2017 ( Subtotal = $369,580 )
2017	2017	Q-STATE BIOSCIENCES, INC.	179 SIDNEY ST	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cardiovascular Diseases Research	000	3	3/22/2017	NON-COMPETING CONTINUATION	$369,580
														Subtotal = $369,580

Issue Date FY: 2016 ( Subtotal = $602,645 )
2016	2016	Q-STATE BIOSCIENCES INC	43 LINNAEAN STREET	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cardiovascular Diseases Research	000	2	3/22/2016	COMPETING CONTINUATION	$602,645
														Subtotal = $602,645

Grand Total All Awards = $972,225

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High-throughput, all-optical assay in human cardiomyoctes for clinically relevant prediction of drug induced cardiotoxity.

Award Number: R44HL126314

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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