Vector Identification and Gene Delivery Approach in Pigs

描述(由申请人提供)：心力衰竭(HF)是一个巨大的临床问题，需要有效的治疗方法。尽管心力衰竭的传统治疗方法取得了进展，包括药物治疗、心肌血管重建术、机械辅助装置和移植，但心力衰竭仍然是全球主要的死亡原因。因此，一种旨在降低心力衰竭的发病率和死亡率，并提高数百万患者生活质量的新疗法尤为吸引人。 人类衰竭心脏松弛时肌浆网钙摄取不足与肌浆网钙离子ATP酶(SERCA2a)的表达和活性降低以及心脏的收缩能力降低有关。我们以前已经证明：1)腺病毒基因转移是将SERCA2a基因导入体外和活体以及现在猪的心肌细胞中的有效手段，2)增加SERCA2a基因的表达可以恢复压力超负荷肥厚啮齿动物模型的收缩能力和正常的细胞内钙循环，3)腺病毒基因转移到从衰竭的人心脏分离的心肌细胞可以恢复收缩和松弛特性。 为了开发SERCA2a作为治疗靶点，还需要完成以下工作：1)必须选择合适的载体和启动子，2)必须在两个物种上进行有效性、安全性和毒性研究。我们已经在一定程度上解决了适当载体的选择，开发了一种传递方法，并展示了在我们的第一阶段应用期间展示有效性的早期概念验证研究。必须对两种动物(一种啮齿动物和一种非啮齿动物)进行研究，以获得FDA的批准。希望通过研究这种治疗分子变力的新疗法，该公司将能够验证SERCA2a作为治疗目标。在这里，我们建议进行必要的研究，使我们能够应对FDA要求的任何其他研究，这些研究将要求我们在第三阶段资金结束时提交成功的研究性新药申请。

DESCRIPTION (provided by applicant): Heart failure (HF) represents an enormous clinical problem demanding effective therapeutic approaches. Despite advances in traditional approaches to its treatment, including pharmacological management, myocardial revascularization, mechanical assist devices, and transplantation, heart failure remains a leading cause of death worldwide. Therefore, a novel therapy aimed at decreasing the morbidity and mortality of heart failure and at improving the quality of life for millions of patients is particularly attractive. Deficient calcium uptake by the sarcoplasmic reticulum during relaxation in failing hearts from humans has been associated with a decrease in the expression and activity of SR Ca2+ATPase (SERCA2a) and contractility of the heart. We have previously demonstrated that: 1) adenoviral gene transfer is an effective means of introducing the SERCA2a gene into myocytes in vitro and in vivo in rodents and now in pigs, 2) that increasing the expression of SERCA2a restores contractility and normalizes intracellular calcium cycling in a rodent model of pressure-overload hypertrophy and 3) that adenoviral gene transfer to cardiac myocytes isolated from failing human hearts results in restoration of contraction and relaxation properties. In order to develop SERCA2a as a therapeutic target the following remains to be accomplished: 1) the proper vector and promoter must be selected, and 2) efficacy, safety, and toxicity studies must be performed in two species. We have addressed in part the selection of the proper vector, developed a delivery method as well as demonstrated early proof of concept studies showing efficacy during our Phase 1 application. Two species (one rodent and one non-rodent) must be studied for FDA approval. It is hoped that by examining this novel therapy for molecular inotropy, the company will be able to validate SERCA2a as a therapeutic target. Here, we propose to perform needed studies that will position us for any additional studies requested by the FDA which would be required to file a successful Investigational New Drug application at the end of Phase 3 funding.