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RSK3 Anchoring Disruptor Therapy for Heart Failure

Award Number: R44HL167349
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/14/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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RSK3 Anchoring Disruptor Therapy for Heart Failure - Novel therapeutic approaches are desperately needed in an expanding patient population to improve both the survival and quality of life for patients with or susceptible to heart failure. Research over the last two decades has established p90 ribosomal S6 kinase type 3 (RSK3) as a pivotal regulator of pathological cardiac remodeling, including in mouse models of pressure overload and genetic cardiomyopathy. RSK3 is required for pathological remodeling even though RSK3 is less abundant in the cardiac myocyte than other members of the RSK protein kinase family. The efficiency and specificity of intracellular signal transduction can be enhanced by the anchoring and co-localization of key enzymes and their upstream activators and substrate effectors by scaffold proteins. RSK3’s unique N-terminal domain confers high affinity binding to the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) in the cardiac myocyte. Recently published data show that blockade of RSK3 association with mAKAPβ by adeno-associated virus (AAV) mediated expression of the mAKAPβ-derived RSK3 Binding Domain (RBD) anchoring disruptor polypeptide will inhibit the development of pathological remodeling and heart failure during chronic pressure overload in the mouse. Newer data demonstrate that RBD expression will also prevent remodeling following myocardial infarction (MI) in the mouse. Cardiac RSK3 Inhibitors, LLC (CRI Biotech) is a company developing patent-protected therapeutics targeting cardiac myocyte mAKAPβ signalosomes for the prevention and/or treatment of heart failure. To target mAKAPβ-RSK3-dependent signaling via blockade of the mAKAPβ-RSK3 protein-protein interaction, CRI Biotech proposes to treat patients at risk for heart failure with the new self-complementary, serotype 9 AAV gene therapy vector AAV9sc.RBD. As a dose sufficient to deliver AAV9sc.RBD with high penetrance to the swine myocardium has been determined, CRI Biotech will now test in this Direct to Phase II SBIR project the efficacy of AAV9sc.RBD in a clinically relevant swine model of ischemic cardiomyopathy. Specific Aim 1: Efficacy of RSK3 anchoring disruptor peptide for post-myocardial infarction heart failure in a large animal model. The core of this project is to test whether RBD peptide expression will reduce pathological remodeling induced by MI in swine, preventing heart failure. Swine will be subjected to ischemia-reperfusion injury to induce MI and then treated immediately afterwards with AAV9sc.RBD by antegrade intracoronary infusion. Cardiac function will be assessed serially for 12 weeks post- MI. Specific Aim 2: AAV9sc.RBD-mediated inhibition of the molecular and cellular pathology associated with heart failure. Taking advantage of tissue collected from the same animals used in Specific Aim 1, the benefits of the RBD anchoring disruptor biologic in swine will be further demonstrated by gravimetric, histological, and molecular analyses for fibrosis and other markers of cardiac remodeling and heart failure. In addition, initial toxicology screens will be done to test AAV9sc.RBD safety.


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 = $0 )
2026	2024	CRI BIOTECH, INC	24133 YOUNG CT	LOS ALTOS	CA	94024	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	2/19/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	CRI BIOTECH, INC	24133 YOUNG CT	LOS ALTOS	CA	94024	SANTA CLARA	USA	Cardiovascular Diseases Research	001	2	2/26/2025	NON-COMPETING CONTINUATION	$1,227,614
2025	2024	CRI BIOTECH, INC	24133 YOUNG CT	LOS ALTOS	CA	94024	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	2/21/2025	NON-COMPETING CONTINUATION	-$1,227,614
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,982,787 )
2024	2024	CARDIAC RSK3 INHIBITORS LLC	24133 YOUNG CT	LOS ALTOS	CA	94024	SANTA CLARA	USA	Cardiovascular Diseases Research	001	2	7/15/2024	NON-COMPETING CONTINUATION	$1,982,787
2024	2023	CARDIAC RSK3 INHIBITORS, LLC	24133 YOUNG COURT	LOS ALTOS	CA	94024	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	10/19/2023	NEW	$0
														Subtotal = $1,982,787

Issue Date FY: 2023 ( Subtotal = $1,978,293 )
2023	2023	CARDIAC RSK3 INHIBITORS, LLC	24133 YOUNG COURT	LOS ALTOS	CA	94024	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	9/14/2023	NEW	$1,978,293
														Subtotal = $1,978,293

Grand Total All Awards = $3,961,080

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RSK3 Anchoring Disruptor Therapy for Heart Failure

Award Number: R44HL167349

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/14/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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