Final preclinical development of gene therapy for post-operative atrial fibrillat

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

DESCRIPTION (provided by applicant): Post-operative atrial fibrillation (POAF) is the most common complication following cardiac surgery. POAF increases morbidity and mortality after surgery, increases length of stay in the ICU and hospital, and increases risks of stroke, congestive heart failure, myocardial infarction and death. The impact on public health is substantial. In particular, POAF is a problem of the elderly, because the need for cardiac surgery, and the incidence, morbidity and mortality of POAF all increase as a function of age. Currently available preventative strategies still allow a 30% incidence of POAF. To combat this problem, we propose gene therapy as a new strategy to prevent POAF. We have efficacy and safety data in a pig model of POAF that shows prevention of sustained AF for 2 weeks after atrial gene painting of AdKCNH2-G628S, a time that coincides with the window of risk for POAF. We saw no proarrhythmia or other negative effects after atrial gene painting. Here, we propose formal preclinical testing of AdKCNH2-G628S with the following specific aims: (1) to successfully complete a dose-ranging study that defines minimum effective dose, and (2) to successfully complete a formal preclinical biodistribution and toxicology testing that defines maximum safe dose. Successful completion of these aims will complete the necessary preclinical testing before moving this potential life-saving therapy to clinical trial.