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Novel targeted modified mRNA delivery in Donation After Circulatory Death Heart Transplantation

Award Number: R01HL181085
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Novel targeted modified mRNA delivery in Donation After Circulatory Death Heart Transplantation - PROJECT SUMMARY Heart transplant surgery is the only definitive therapy for end-stage heart disease. As the number of patients on the transplant waitlist continues to rise, the supply of suitable heart donors remains insufficient. To address this, normothermic regional perfusion (NRP), a type of cardiopulmonary bypass, and ex vivo machine perfusion being used to reanimate hearts from donation after after circulatory death (DCD) donors prior to transplantation. A significant adverse event after heart transplantation is primary graft dysfunction (PGD); an ischemia-reperfusion injury (IRI) induced cellular injury and tissue degradation play a significant role in PGD which occurs in ~35% of transplants. Paradoxically, in an effort to expand the donor pool, donors with prolonged warm ischemic time, and DCD donors are being increasingly utilized to meet the unmet volume demand with some centers utilizing 30% DCD and NRP or ex vivo perfusion being a resuscitative strategy. One of the central causes of pathophysiology observed in PGD is a hyper-inflammatory response to IRI which results in cellular and tissue injury because of neutrophil driven pyroptosis. Therefore, therapies directed toward mitigating the pyroptotic response to IRI are of interest in treating PGD. MG53 is an essential component of the cell membrane repair machinery, serving as a molecular bandage to facilitate the repair of multi-tissue injuries. The recombinant human MG53 (rhMG53) protein protects cardiomyocytes and mitigates inflammation. Modulating pyroptosis can directly regulate inflammation and indirectly regulate cell survival may have therapeutic potential in heart transplantation. This approach is novel and has not been investigated. Uncovering of the mechanistic roles of pyroptosis in triggering acute PGD and its impact on chronic immune system priming highlights the potential of MG53 as a therapeutic intervention to improve DCD heart transplant outcomes. Based on pilot data, we hypothesized that ischemic injury and immune cell pyroptosis are key events lead to heart transplantation failure, MG53 plays dual roles in promoting cardiac tissue integrity and inhibiting post-transplant inflammation to improve success of heart transplantation. We will interrogate this hypothesis by elucidating molecular mechanisms of MG53-mediated pyroptosis regulation in heart transplantation relevant IRI. Additionally, we will define the role of pyroptosis inhibition to preserve immune cells survival after IRI, mitigating intercellular signaling with potential therapeutic benefit in heart transplantation utilizing NRP or ex vivo heart perfusion to deliver MG53 to reanimate and resuscitate the donor allograft. Furthermore, functional interactions between MG53 and GsdmD will be evaluated. Accomplishing the aims of this proposal will increase the mechanistic understanding of intrinsic heart donor allograft biology after recovery and the integral role of pyroptotic cell death in response to IRI which results in PGD.


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: 2026 ( Subtotal = $1,574,578 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	1	6/25/2026	NEW	$1,574,578
														Subtotal = $1,574,578

Grand Total All Awards = $1,574,578

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Novel targeted modified mRNA delivery in Donation After Circulatory Death Heart Transplantation

Award Number: R01HL181085

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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