Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Understanding and Controlling the Contribution of Fibrinolysis to Bleeding Using a Long-Acting Antifibrinolytic RNA Therapy

Award Number: R01HL166382
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

Group Awards By:

View Award Description

Understanding and Controlling the Contribution of Fibrinolysis to Bleeding Using a Long-Acting Antifibrinolytic RNA Therapy - SUMMARY BACKGROUND: The balance between clot formation (coagulation) and degradation (fibrinolysis) is disrupted in patients with bleeding disorders or severe hemorrhage, resulting in increased bleeding. The extent to which fibrinolysis contributes to bleeding from the onset of acute bleeding in these contexts is unclear, and this gap in knowledge limits the development of therapies that inhibit fibrinolysis. Current therapeutics are often not sufficient for patients with bleeding disorders; for example, antifibrinolytic drugs are widely used to manage acute bleeding in these patients, but are unsuitable for long-term prophylaxis due to short half-lives that decrease efficacy. RATIONALE: We hypothesize that fibrinolysis contributes to the incidence and severity of bleeding starting from the onset of bleeding, and that long-acting RNA agents targeting plasminogen, the zymogen precursor of the main fibrinolytic enzyme plasmin, can decrease fibrinolysis and help manage bleeding long-term for people across all classes of bleeding disorders, including diagnosed and undiagnosed disorders. This knowledge will provide insights into the mechanisms that impact outcomes in traumatic hemorrhage. These RNA agents will be delivered using lipid nanoparticles (LNPs), a clinically approved delivery platform we have unique expertise in. SPECIFIC AIMS: We will develop an RNA therapeutic targeting plasminogen, using small interfering RNA (siRNA)-mediated gene silencing (siPlg). This therapy is long-acting over several weeks per dose and highly specific for the target protein, which decreases the burden of frequent administration. The specific aims of this proposal are to (1) Develop approaches for knockdown of plasminogen and inhibition of fibrinolysis in mice, pigs, and dogs, and characterize the safety of this approach; (2) Determine the contribution of fibrinolysis to blood loss at the onset and in early stages of hemorrhage in a traumatic injury model in swine; and (3) Investigate the role of fibrinolysis in bleeding disorders by testing the effect of plasminogen knockdown in mouse and canine models of hemophilia A, and mouse models of hemophilia B and von Willebrand disease. INNOVATION: This work has both mechanistic and therapeutic innovation. It will immediately determine the contribution of fibrinolysis to bleeding in early stages of severe hemorrhage and in bleeding disorders. This will likely be the first development of RNA-LNP therapies targeting circulating proteins in large animal models of bleeding. These findings will address a fundamental question in trauma and hemostasis research. Separately, it will aid the development of improved, long-acting therapies for controlling bleeding in bleeding disorders. These therapies would be particularly beneficial for women with menorrhagia caused by bleeding disorders. EXPECTED OUTCOMES: We expect to (1) Develop species-specific siPlg that have minimal adverse health effects; and (2-3) Demonstrate that knocking down plasminogen inhibits fibrinolysis and decreases blood loss in swine models of traumatic hemorrhage, and in murine and canine models of bleeding disorders.


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 = $718,283 )
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	3	7/23/2025	NON-COMPETING CONTINUATION	$718,283
2025	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	2	3/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $718,283

Issue Date FY: 2024 ( Subtotal = $707,172 )
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	2	7/5/2024	NON-COMPETING CONTINUATION	$707,172
														Subtotal = $707,172

Issue Date FY: 2023 ( Subtotal = $757,275 )
2023	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	1	8/15/2023	NEW	$757,275
														Subtotal = $757,275

Grand Total All Awards = $2,182,730

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Understanding and Controlling the Contribution of Fibrinolysis to Bleeding Using a Long-Acting Antifibrinolytic RNA Therapy

Award Number: R01HL166382

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer