PP2A Anchoring Disruptor Therapy in Heart Failure

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 therapy will be further demonstrated by gravimetric, histological, and molecular analyses.Heart failure is a syndrome of major public health significance that contributes to the death of about 1 in 8 Americans. Despite a range of existing therapies, the mortality rate for patients with heart failure is high, with nearly 50% of patients dying within 5 years of a diagnosis. In this application, we aim to develop a new therapy for heart failure based upon selectively targeting the anchoring of PP2A to the scaffold protein mAKAPβ.