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Targeting Junctophilin-2 for heart failure gene therapy

Award Number: R01HL177305
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/18/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Targeting Junctophilin-2 for heart failure gene therapy - ABSTRACT Heart failure (HF) is a complex, progressive, and lethal disease that has no cure. Hypertension and myocardial infarction are two major risk factors for HF that place prolonged stress on the heart. The combination of cardiomyocyte hypertrophy, cell death, increased fibrosis, and other maladaptive structural remodeling events can then lead to cardiac decompensation and eventually death. At the cellular / molecular levels, HF (with reduced ejection fraction) is characterized by impaired excitation-contraction (E-C) coupling function and maladaptive transcriptional reprogramming. Current interventions remain inadequate in treating HF partly because few have been directed at correcting the maladaptive mechanisms within cardiomyocytes that initiate and mediate cardiac remodeling events. This proposal seeks to overcoming barriers in HF treatment by developing novel gene therapies that are effective in restoring both normal E-C function and gene transcription. Our prior work points to Junctophilin-2 (JP2) as a critical structural determinant of E-C coupling function under baseline conditions and as a salutary stress-adaptive transcriptional repressor in response to cardiac stress. JP2 becomes site-specifically cleaved by stress-responsive and Ca2+-dependent calpain proteases that generates a nuclear translocating N-terminal fragment (JP2NT) that functions to repress HF-related transcripts. We have demonstrated that adeno-associated virus expressing JP2NT (AAV-JP2NT) are therapeutic in attenuating HF from pressure overload stress. Our recent data show that knock-in mice expressing a calpain-resistant mutant of JP2 (JP2CR) are also protected from HF primarily by improving E-C coupling function. By leveraging the recently developed, optimized MyoAAV system, we hypothesize that HF outcomes can be improved through single MyoAAV-JP2CR gene therapy that sustains E-C coupling function, and that even better outcomes can be achieved through a combined strategy using MyoAAV-JP2CR plus MyoAAV-JP2NT dual gene therapy, which provides synergistic benefits by targeting both E-C coupling and transcriptional mechanisms. In Aim 1, we will use the optimized, muscle-tropic MyoAAV capsid system and develop cardiac specific and clinically translatable MyoAAV-JP2CR virus for assessing their efficacy in attenuating HF progression in mice in response to pressure overload and ischemic stresses. In Aim 2, we will test whether combination therapy with MyoAAV-JP2CR and MyoAAV-JP2NT is more effective as a HF gene therapy approach than either alone. Success of this project will have far-reaching implications by not only demonstrating effective HF abrogation by targeting different maladaptive cellular mechanisms but also to establish combination gene therapy as a superior treatment option for guiding future precision medicine in HF patients.


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 = $631,543 )
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	1	6/23/2026	NEW	$631,543
														Subtotal = $631,543

Grand Total All Awards = $631,543

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Targeting Junctophilin-2 for heart failure gene therapy

Award Number: R01HL177305

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/18/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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