Preclinical gene therapy development for post-operative atrial fibrillation

描述（由申请人提供）：术后房颤（POAF）是心脏手术后最常见的并发症。POAF增加了术后发病率和死亡率，增加了ICU和医院的住院时间，并增加了卒中、充血性心力衰竭、心肌梗死和死亡的风险。对公众健康的影响是巨大的。POAF尤其是老年人的问题，因为对心脏手术的需求以及POAF的发病率、发病率和死亡率都随着年龄的增加而增加。目前可用的预防策略仍然允许POAF的发生率为30%。为了解决这个问题，我们提出基因治疗作为预防POAF的新策略。我们在POAF的猪模型中获得了有效性和安全性数据，该数据显示AdKCNH 2-G628 S的心房基因涂绘后持续AF的预防持续2周，该时间与POAF的风险窗口一致。心房基因涂绘后，我们没有看到致心律失常或其他负面影响。在此，我们建议对AdKCNH 2-G628 S进行正式的临床前试验，具体目标如下：（1）成功完成定义最小有效剂量的剂量范围研究，以及（2）成功完成定义最大安全剂量的正式临床前生物分布和毒理学试验。成功完成这些目标将完成必要的临床前测试，然后将这种潜在的挽救生命的疗法推向临床试验。

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.