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Mechanisms of corticosteroids in dystrophic cardiomyopathy

Award Number: R01HL153054
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Mechanisms of corticosteroids in dystrophic cardiomyopathy - Corticosteroids provide an important drug class for treatment of numerous forms of heart failure and chronic inflammation, together affecting over 432 million people. In Duchenne muscular dystrophy (DMD), drugs that target corticosteroid receptors are used to treat heart and skeletal muscle. Our lab developed a first-in-class dissociative steroid that shows efficacy as both a heart-protective and anti-inflammatory drug. Our work in the mdx mouse model of DMD was critical for moving this drug, vamorolone, into DMD clinical trials (now in Phase 2b). In early cell and animal studies, vamorolone showed anti-inflammatory efficacy while avoiding key side effects. Subsequently, we discovered new readouts of drug activity and important impacts of corticosteroids on dystrophic hearts. Cardiomyopathy is a feature of both the severe muscle disease DMD (caused by loss of dystrophin) and the milder muscle disease Becker muscular dystrophy (dystrophin in-frame deletions). As promising new therapies are being developed that seek to convert severe DMD genotypes into milder Becker- like phenotypes, importance of treating dystrophic hearts should grow because cardiomyopathy is the leading cause of Becker mortality. Moving forward, it will be important to address knowledge gaps regarding the mechanisms of selective steroids, roles of specific steroid receptors in the heart, and impacts of steroids on Becker-like hearts. This knowledge is important because cardiomyopathy is a leading cause of DMD mortality and current corticosteroids have problematic safety profiles. Our long-term goal is to dissect mechanisms of steroid signaling that can be selectively targeted to improve treatment of chronic pediatric diseases. This can greatly improve outcomes for DMD in a way that also impacts much larger groups of heart, muscle and inflammatory diseases. The objective of this grant is to dissect mechanisms of corticosteroid receptors that impact dystrophic cardiomyopathy. The advanced expertise and tools developed by our lab place us in a unique position to accomplish this using a combination of cell culture, receptor mutation, tissue-specific knockout, micro-dystrophin gene therapy, and animal model systems. We propose the central hypothesis that 11β-hydroxysteroid agonists activate receptor transactivation to drive progression of dystrophic heart pathology. Our rationale is that identifying corticosteroid mechanisms which can be selectively targeted will provide a basis for the improved treatment of DMD and other diseases with heart failure or chronic inflammation.


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	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	001	5	3/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$64,323
2025	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	4	3/19/2025	NON-COMPETING CONTINUATION	-$64,323
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $388,125 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	002	6	7/9/2024	NON-COMPETING CONTINUATION	$388,125
2024	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	-$370,204
2024	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	5	4/4/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$370,204
														Subtotal = $388,125

Issue Date FY: 2023 ( Subtotal = $446,250 )
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	4	7/31/2023	NON-COMPETING CONTINUATION	$446,250
														Subtotal = $446,250

Issue Date FY: 2022 ( Subtotal = $446,250 )
2022	2022	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	3	7/20/2022	NON-COMPETING CONTINUATION	$446,250
														Subtotal = $446,250

Issue Date FY: 2021 ( Subtotal = $446,250 )
2021	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	2	8/5/2021	NON-COMPETING CONTINUATION	$446,250
														Subtotal = $446,250

Issue Date FY: 2020 ( Subtotal = $446,250 )
2020	2020	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	1	7/17/2020	NEW	$446,250
														Subtotal = $446,250

Grand Total All Awards = $2,173,125

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Mechanisms of corticosteroids in dystrophic cardiomyopathy

Award Number: R01HL153054

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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