Vector Identification and Gene Delivery Approach in Pigs

猪的载体鉴定和基因传递方法

• 批准号: 7054234
• 负责人: Judith K Gwathmey
• 金额: $ 161.3万
• 依托单位: GWATHMEY, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-10 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054234
• 关键词: DNA damage; adeno associated virus group; animal mortality; biotechnology; calcium transporting ATPase; cytomegalovirus; cytotoxicity; electron microscopy; gene delivery system; gene expression; gene therapy; genetic promoter element; heart failure; heart function; heart ventricle; hemodynamics; immunocytochemistry; in situ hybridization; laboratory rat; myocardial ischemia /hypoxia; nonhuman therapy evaluation; polymerase chain reaction; sarcoplasmic reticulum; swine; therapy adverse effect; transfection /expression vector; troponin

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.

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。尽管传统的治疗方法（包括药物管理、心肌血运重建、机械辅助装置和移植）取得了进步，但心力衰竭仍然是全世界死亡的主要原因。因此，旨在降低心力衰竭发病率和死亡率并改善数百万患者生活质量的新疗法特别有吸引力。 人类衰竭心脏舒张期间肌浆网钙摄取不足与 SR Ca2+ ATP 酶 (SERCA2a) 表达和活性以及心脏收缩力的降低有关。我们之前已经证明：1) 腺病毒基因转移是将 SERCA2a 基因导入体外和体内的啮齿类动物和猪的肌细胞的有效方法，2) 增加 SERCA2a 的表达可恢复心肌细胞的收缩性并使细胞内钙循环正常化。压力超负荷肥大的啮齿动物模型；3）将腺病毒基因转移到从衰竭的人类心脏中分离出来的心肌细胞中，导致收缩和松弛特性的恢复。 为了将SERCA2a开发为治疗靶点，还需要完成以下工作：1）必须选择合适的载体和启动子，2）必须在两个物种中进行功效、安全性和毒性研究。我们已经部分解决了正确载体的选择问题，开发了一种递送方法，并展示了在我们的第一阶段应用中显示功效的早期概念验证研究。必须对两种物种（一种啮齿动物和一种非啮齿动物）进行研究才能获得 FDA 批准。希望通过检查这种新的分子正性肌力疗法，该公司将能够验证 SERCA2a 作为治疗靶点。在这里，我们建议进行必要的研究，这将使我们能够进行 FDA 要求的任何额外研究，这些研究需要在第 3 阶段资助结束时成功提交研究性新药申请。