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Exosome-based therapeutics for heart failure

Award Number: R01HL124074
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/11/2014
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Exosome-based therapeutics for heart failure - Project Summary/Abstract Cardiosphere-derived cells (CDCs) exert strong disease-modifying activity in various models of heart failure. In the original funding period of this R01, we tested, and ended up supporting, the hypothesis that the therapeutic benefits of CDCs are mediated by exosomes (nanosized lipid bilayer vesicles that are enriched in noncoding RNAs). Indeed, the concepts first articulated here for heart-derived cells have since been generalized to virtually all other cell types under development as therapeutic candidates for heart failure; even pluripotent stem cell products are now acknowledged to act largely via exosome secretion. We and others have also established that many, if not most, of the effects of exosomes are mediated by their RNA contents, specifically miRs and other noncoding RNAs (ncRNAs). The emerging paradigm is as follows: CDCs secrete exosomes which transfer payloads into target cells, inducing transcriptomic and phenotypic changes that underlie the benefits of CDC therapy. As a corollary of our work to define mechanisms of action of cardiac cell therapy, we have come to realize that exosomes are themselves viable next-generation therapeutic candidates. Potential advantages over the parent cells include product stability, immune tolerability, and the ability to achieve efficacy with simple intravenous (IV) administration. The major focus of the first funding period was on unaltered exosomes produced by primary wild type CDCs. In this competitive renewal, we will manipulate exosomes both by alterations of the parent cell and directly, after isolation. Such manipulation can increase potency as well as improve targeting. Technological and conceptual advances now make it possible to envision a novel, stable, cell-free therapeutic agent that can effectively target heart failure when delivered IV. Here we propose to develop trenchant methods to assess exosome biodistribution, to enhance exosome targeting and potency, and to immortalize CDCs as a stable source of therapeutic exosomes. The specific aims are designed to answer four inter-connected questions: What is the biodistribution of exosomes when delivered IV (Aim 1)? Can we facilitate tissue/cell-directed targeting of exosomes when delivered IV (Aim 2)? Can we immortalize CDCs to generate therapeutically potent and consistent exosomes (Aim 3)? Combining the insights from these various approaches, can we create and select a therapeutic candidate of optimal efficacy for modifying heart failure in vivo after IV administration (Aim 4)? We will create useful models (fate-mapping mTmG mice) and methods (exosomal Cre loading, targeting strategies, CDC immortalization) which will advance our mechanistic understanding of exosome biology. Meanwhile, the proposed work constitutes an important translational step towards the development of exosomes as off-the- shelf therapeutic candidates. CDCs are already in advanced clinical testing, but living cells have limitations relative to cell-free products. Thus, our proposal, focusing on genetically-enhanced exosomes (as cell-free derivatives of immortalized CDCs), opens up new treatment options for heart failure.


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	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	8	12/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $562,482 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	001	8	5/19/2021	NON-COMPETING CONTINUATION	$56,248
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	8	1/21/2021	NON-COMPETING CONTINUATION	$506,234
														Subtotal = $562,482

Issue Date FY: 2020 ( Subtotal = $526,533 )
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	001	7	3/7/2020	NON-COMPETING CONTINUATION	$26,328
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	7	1/17/2020	NON-COMPETING CONTINUATION	$500,205
														Subtotal = $526,533

Issue Date FY: 2019 ( Subtotal = $634,766 )
2019	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	6	2/25/2019	NON-COMPETING CONTINUATION	$634,766
														Subtotal = $634,766

Issue Date FY: 2018 ( Subtotal = $540,824 )
2018	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	002	5	8/20/2018	COMPETING CONTINUATION	$162
2018	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	5	5/4/2018	COMPETING CONTINUATION	$540,824
2018	2017	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	001	4	8/20/2018	NON-COMPETING CONTINUATION	-$162
														Subtotal = $540,824

Issue Date FY: 2017 ( Subtotal = $425,000 )
2017	2017	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	4/27/2017	NON-COMPETING CONTINUATION	$425,000
														Subtotal = $425,000

Issue Date FY: 2016 ( Subtotal = $425,000 )
2016	2016	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	4/29/2016	NON-COMPETING CONTINUATION	$425,000
														Subtotal = $425,000

Issue Date FY: 2015 ( Subtotal = $418,625 )
2015	2015	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	4/6/2015	NON-COMPETING CONTINUATION	$418,625
														Subtotal = $418,625

Issue Date FY: 2014 ( Subtotal = $425,000 )
2014	2014	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	7/11/2014	NEW	$425,000
														Subtotal = $425,000

Grand Total All Awards = $3,958,230

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Exosome-based therapeutics for heart failure

Award Number: R01HL124074

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/11/2014

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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