# PP2A Anchoring Disruptor Therapy in Heart Failure

> **NIH NIH R44** · CARDIAC RSK3 INHIBITORS, LLC · 2022 · $1,888,812

## Abstract

Pathological cardiac remodeling constitutes a common pathway to heart failure in disease. Despite
current pharmacologic therapy and other advances that attenuate remodeling, morbidity and mortality due to
heart failure remain high. 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, mainly in the academic laboratory of Dr. Michael S. Kapiloff, has established the 230
kDa scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) as the organizer of multimolecular signaling
complexes critical in the cardiac myocyte for the induction and progression of pathological cardiac remodeling.
One constituent of mAKAPβ “signalosomes” is protein phosphatase 2A (PP2A) that contains the B56δ
(PPP2R5D) regulatory subunit. New preliminary data show that mAKAPβ-bound PP2A regulates myocyte
elongation and ventricular dilation in disease. Observations that B56δ expression is elevated in human and
canine heart failure support the candidacy of mAKAPβ-bound PP2A as a target for intervention in the treatment
of non-ischemic and ischemic dilated cardiomyopathies. Cardiac RSK3 Inhibitors, LLC (CRI Biotech) is a
company founded by Dr. Kapiloff that is developing patent-protected therapeutics targeting cardiac myocyte
mAKAPβ signalosomes for the prevention and/or treatment of heart failure. To target mAKAPβ-PP2A complexes
via blockade of PP2A-mAKAPβ protein-protein interaction, CRI Biotech is developing a new self-complementary,
adeno-associated virus serotype 9 (AAV9sc) gene therapy vector. Preliminary data in mice shows that treatment
with this vector results in restoration and long term preservation of cardiac structure and function following
myocardial infarction. CRI Biotech proposes that this gene therapy constitutes a novel approach for the
prevention and/or treatment of pathological ventricular dilation and eccentric hypertrophy, with potentially broad
efficacy across diverse cardiovascular diseases. In this Fast-Track SBIR application, CRI Biotech will test the
efficacy of the new biologic in a clinically relevant swine model of ischemic cardiomyopathy, as a pivotal efficacy
study and key step on the path to first-in-human clinical trials. Phase I - The milestone for this Aim is the
determination of the minimum AAV9sc dose required for consistent inhibition of PP2A anchoring to mAKAPβ in
the heart, thereby defining the appropriate biologic dose to be used for efficacy testing in Phase II. Phase II -
Specific Aim 1: Efficacy of the new gene therapy for post-myocardial infarction heart failure in a large animal
model. The core of this project is to test whether the new AAV9sc-based gene therapy will reduce pathological
remodeling induced by MI in swine, preventing heart failure. Specific Aim 2: Taking advantage of tissue collected
from the same animals used in Aim 1, the benefits of the new gene...

## Key facts

- **NIH application ID:** 10510778
- **Project number:** 4R44HL158318-02
- **Recipient organization:** CARDIAC RSK3 INHIBITORS, LLC
- **Principal Investigator:** Federico Cividini
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,888,812
- **Award type:** 4N
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10510778

## Citation

> US National Institutes of Health, RePORTER application 10510778, PP2A Anchoring Disruptor Therapy in Heart Failure (4R44HL158318-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10510778. Licensed CC0.

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