# ShRNA-Based Targeting of mAKAPβ in Heart Failure

> **NIH NIH R44** · CARDIAC RSK3 INHIBITORS, LLC · 2021 · $1,761,984

## Abstract

Pathological cardiac remodeling constitutes a common pathway to heart failure in disease. Despite current
pharmacologic therapy and other advances that attenuate remodeling, mortality due to heart failure remains
high. New, more effective therapeutic options are desperately needed in an increasing patient population to
improve both the survival and quality of life for patients with or susceptible to heart failure. Muscle A-kinase
anchoring protein β (mAKAPβ) is the organizer of multimolecular signaling complexes critical for the induction
and progression of pathological cardiac remodeling. By binding a diverse set of signaling molecules, mAKAPβ
dynamically orchestrates multiple signaling modules that transduce cAMP, mitogen-activated protein kinase
(MAPK), Ca2+, phosphoinositide, and hypoxic stress signals. Accordingly, cardiomyocyte-specific mAKAPβ
knock-out in mice inhibited remodeling and the development heart failure in multiple models of cardiovascular
disease. CRI is a company developing novel, patent protected therapeutics for the prevention and/or treatment
of heart failure. In this Fast-Tract SBIR, CRI will test a new gene therapy vector designed to inhibit mAKAPβ
expression selectively in the cardiac myocyte by RNA interference. The AAV9sc.shmAKAP biologic is a self-
complementary, cardiotropic, serotype 9 adeno-associated virus (AAV9) that expresses an mAKAP-specific
small hairpin RNA (shRNA) under the control of a cardiac myocyte-specific promoter. In this application, CRI will
test the new biologic in a clinically relevant large animal model for post-myocardial infarction (MI) heart failure.
Phase I - Specific Aim: We will perform a dose response curve for the biologic in Yorkshire swine to determine
the minimum dose required for consistent inhibition of mAKAPβ expression in the heart. Phase II - Specific Aim
1: Efficacy of mAKAP RNAi for heart failure in a large animal model. The core of this project is to test
whether mAKAPβ RNAi will mitigate pathological remodeling induced by MI in swine, preventing heart failure.
Swine will be subjected to ischemia-reperfusion to induce MI or sham procedure and then treated with the
AAV9sc.shmAKAP biologic by intracoronary infusion immediately after or 1 month later at the dose determined
in Phase I. The pigs will be followed by serial echocardiography and studied at endpoint 3 months post-MI by
catheterization for left ventricular pressure-volume loop hemodynamics. The goal for this Aim is the
demonstration that mAKAP RNAi will preserve cardiac structure and function in a large animal model of MI
disease. Specific Aim 2: AAV9sc.shmAKAP-mediated inhibition of the molecular and cellular pathology
associated with heart failure. Taking advantage of tissue collected from the same animals used in Aim 1, the
benefits of mAKAP RNAi in swine will be demonstrated by gravimetric, histological, and molecular analyses for
fibrosis and other markers of cardiac remodeling and heart failure. In addition, initi...

## Key facts

- **NIH application ID:** 10378267
- **Project number:** 4R44HL147631-02
- **Recipient organization:** CARDIAC RSK3 INHIBITORS, LLC
- **Principal Investigator:** Federico Cividini
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,761,984
- **Award type:** 4N
- **Project period:** 2019-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378267

## Citation

> US National Institutes of Health, RePORTER application 10378267, ShRNA-Based Targeting of mAKAPβ in Heart Failure (4R44HL147631-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10378267. Licensed CC0.

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