Improved Dosing and Refinement of a Cardiac Targeted Gene Therapy in a Swine Infarct Model

DESCRIPTION provided by applicant Title Improved Dosing and Refinement of a Cardiac Targeted Gene Therapy in a Swine Heart Failure Model Abstract The goal of this Direct to Phase II SBIR is to build on prior progress developing BB R gene therapy for heart failure to increase the scale of vector production and using GMP to support IND enabling studies and clinical trials expand beyond the POC data performing a nd pig infarct heart failure study with more statistical power and a longer period infarct and treatment improve the delivery and distribution in the heart and generate additional efficacy and safety data needed for progression to clinical studies and demonstrating that a novel myofilament targeted gene therapy can reduce halt or reverse the decline in cardiac function following myocardial infarction MI and heart failure million Americans suffer MI yearly accounting for most of the andgt annual new cases of diagnosed heart failure HF With the exception of transplantation current treatments are merely palliative and fail to restore cardiac function Thus treatments that halt progression to failure or improve function are needed and could significantly lower healthcare costs especially with an aging US population Dr Michael Regnier a BEATBio Co Founder and Co Investigator has demonstrated that small increases in cardiomyocyte deoxy ATP dATP results in significant enhancement of myofilament contraction His group demonstrated that adenoviral mediated overexpression of ribonucleotide reductase R R increases dATP in adult rat cardiomyocytes resulting in enhanced contraction and faster relaxation without altering Ca release from the sarcoplasmic reticulum SR Thus importantly contraction efficiency of myofilaments is enhanced without altering cardiac Ca cycling A novel aspect of this therapy is that R R overexpressing cardiac cells deliver dATP to non transduced cardiomyocytes via gap junctions increasing their contractility thus indicating not all cardiomyocytes need to be transduced to achieve a therapeutic effect To determine translational efficacy Dr Regnier and colleagues developed an adeno associated viral vector with a cardiac specific promoter cTnT to selectively overexpress both subunits of R R in the heart using a single vector designated BB R AAV R R cTnT BEATBio is developing this technology to treat HF and has made several major advancements demonstrating feasibility In this project we will scale up the manufacturing of GLP grade BB R and to deliver BB R to Yucatan mini pig hearts month following MI via coronary catheterization subsequent to the onset of HF Cardiac function in vivo will be assessed by echocardiography and hemodynamic measurements at baseline pre administration and at and months post administration Hearts will then be removed for morphological and histological assessments vector distribution and expression multiple tissues and cardiac tissue levels of dATP We will also perform a long term study in infarcted mice to determine persistence of efficacy and safety This study will provide information to guide more in depth preclinical studies on dose response safety and efficacy and aid in protocol development for Phase I human trials PUBLIC HEALTH RELEVANCE The work proposed in this application will establish whether a gene therapy that enhances cardiac performance can reverse heart failure in a preclinical large animal heart failure model This treatment has been demonstrated in a smaller proof of concept study to significantly enhance the ability of severely failing hearts to move blood and perform at near normal levels Our translational medicine approach uses proven and safe gene therapy vectors and is aimed at moving this cardiac performance enhancing gene therapy toward the clinic and commercialization