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Vascular, Cardiac, and Lung Alveolar Human Microphysiological Systems for SARS-CoV-2 Drug Screening

Award Number: UH3TR002142
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract The appearance of SARS-CoV-2 in early 2020 has spurred efforts to limit the disease spread and develop effective treatments. The most promising long-term approach is a vaccine. While some vaccines are entering accelerated clinical trials, it may take 12 or more months before an effective vaccine is available. Even if successful, it may not be possible to treat everyone with a vaccine or the effectiveness of the vaccine may be limited. Given the severity of the disease among a number of those patients, alternative approaches to limit infection should be developed. The goal of this proposal is to use human cardiac, vascular, and lung alveolar microphysiological systems (MPS) to identify possible compounds that block SARS-CoV-2 entry into cells and tissues. While cell binding assays can be used to screen drug candidates, human MPS offer the advantage of testing promising drug candidates under conditions encountered in the body. We propose a tiered approach in which primary cells and cells overexpressing angiotensin converting enzyme (ACE2) are used to identify promising candidates that block SARS-CoV-2 virus entry into cells, and vascular, cardiac, and lung alveolar MPS are used to provide a robust evaluation of drugs that block SARS-CoV-2 binding. The first tier with individual cell types enables a rapid screen and the screen with the microphysiological systems enables testing of the most promising candidates with the tissues most likely to be infected. We will develop the screening assays using a pseudovirus with the SARS-CoV-2 spike protein. In Aim 1, we will develop an assay for pseudovirus binding to ACE2 expressing cells by verifying binding and fusion to cells that express ACE2. We will whether the binding specifically involves the spike protein and determine the levels of binding sites on the cell types used in subsequent aims. In Aim 2, we will screen individual cells types for molecules that block entry into the cell of pseudovirus expressing the spike proteins. Potential drug candidates include those that potentially block spike protein binding (e.g. spike proteins, Captopril, Lisinopril, human recombinant soluble ACE2, and antibodies to the spike protein or ACE2) and those inhibiting Transmembrane Serine Protease 2 (TMPRSS2), activity (e.g. camostat mesylate, nafamostat mesylate). In Aim 3, we will test most promising compounds in vascular, cardiac and lung microphysiological systems and compare against results from 2D studies. We will also examine the relationship between drug blocking and factors that affect ACE2 expression.


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 = -$4,565 )
2024	2020	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	National Center for Advancing Translational Sciences	000	4	11/30/2023	SUPPLEMENT FOR EXPANSION	-$4,565
														Subtotal = -$4,565

Issue Date FY: 2023 ( Subtotal = -$5,559 )
2023	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	National Center for Advancing Translational Sciences	000	5	4/5/2023	NON-COMPETING CONTINUATION	-$5,216
2023	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	National Center for Advancing Translational Sciences	001	5	4/5/2023	SUPPLEMENT FOR EXPANSION	-$343
														Subtotal = -$5,559

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	National Center for Advancing Translational Sciences	001	5	1/11/2022	NON-COMPETING CONTINUATION	$0
2022	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	National Center for Advancing Translational Sciences	000	4	10/19/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $1,186,828 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	National Center for Advancing Translational Sciences	002	5	9/1/2021	SUPPLEMENT FOR EXPANSION	$73,266
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	National Center for Advancing Translational Sciences	001	5	6/24/2021	NON-COMPETING CONTINUATION	$1,113,562
2021	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	National Center for Advancing Translational Sciences	000	4	4/2/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,186,828

Issue Date FY: 2020 ( Subtotal = $1,416,241 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	National Center for Advancing Translational Sciences	001	4	8/11/2020	NON-COMPETING CONTINUATION	$1,122,799
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	National Center for Advancing Translational Sciences	002	4	9/3/2020	SUPPLEMENT FOR EXPANSION	$280,600
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	National Center for Advancing Translational Sciences	000	3	3/27/2020	EXTENSION WITH OR WITHOUT FUNDS	$12,842
														Subtotal = $1,416,241

Issue Date FY: 2019 ( Subtotal = $1,374,591 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	National Center for Advancing Translational Sciences	001	3	9/16/2019	SUPPLEMENT FOR EXPANSION	$250,917
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	National Center for Advancing Translational Sciences	000	3	9/5/2019	EXTENSION WITH OR WITHOUT FUNDS	$1,123,674
														Subtotal = $1,374,591

Grand Total All Awards = $3,967,536

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Vascular, Cardiac, and Lung Alveolar Human Microphysiological Systems for SARS-CoV-2 Drug Screening

Award Number: UH3TR002142

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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