Abstract 16778: Design of a Pan Heart Failure Gene Therapy by Targeting Telomere-p53 Axis

Abstract

Introduction: Cardiovascular disease and heart failure is among the top causes of morbidity and mortality worldwide with a critical need for innovative therapies to reverse the course of ventricular dysfunction. We established that heart failure cardiomyocytes exhibit telomere uncapping and shortening, which leads to DNA damage p53 activation and inhibition of mitochondrial biogenesis. Hypothesis: We hypothesize that reprotection of telomeric ends can prevent p53-induced mitochondrial dysfunction and restore cardiac function. Methods: We designed a pan-HF gene therapy (AAV9-modhTERT) - that acts through telomeric reprotection to turn off p53 and restore myocardial mitochondrial biogenesis - and validate safety and efficacy in Ang II and TAC heart failure murine models. Cardiac specificity in human induced pluripotent stem cell derived cardiomyocytes, biodistribution in mice, and dose titration studies on Ang II and TAC mice were performed. Results: One dose of AAV9-modhTERT sufficiently improved ejection fraction by ~20%, prevented cardiac fibrosis and expression of HF biomarkers. Molecularly, AAV9-modTERT blocked DNA damage activation, reversed mitochondrial biogenesis, restored mitochondrial ultrastructure and respiration, and reversed transcriptomic profiles. Conclusions: These preclinical studies demonstrate considerable potential for the first pan-HF single-dose gene therapy that can reverse cardiac function and prevent myocardial remodeling which would be invaluable clinically and an Investigator Initiated Trial (IIT) (NCT05837143) was launched in April 2023.