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）代表了要求有效治疗方法的巨大临床问题。尽管传统的治疗方法取得了进步，包括药理学管理，心肌血运重建，机械辅助设备和移植，但心力衰竭仍然是全球死亡的主要原因。因此，一种旨在降低心力衰竭的发病率和死亡率以及改善数百万患者生活质量的新型疗法特别有吸引力。 人类失败的心脏失败期间肌浆网的钙吸收不足与SR Ca2+ATPase（SERCA2A）的表达和活性降低有关和心脏的收缩力的降低。我们先前已经证明：1）腺病毒基因转移是将SERCA2A基因引入体外和体内啮齿动物和现在的猪体内的肌细胞的有效手段，2）2）增加SERCA2A的表达可恢复收缩力，并在啮齿动物的啮齿动物模型中恢复了辐射型和3），以使我的3层范围内的依赖性和3），该模型的依从性和3），该依从层依从型和3），该模型均匀载体和3），该依从层均匀的依从层依从型和3），该依从层均匀的依从型依从性依从层和3）由于人类心脏失败而导致收缩和放松特性的恢复。 为了将SERCA2A作为治疗靶标开发以下尚待完成：1）必须选择适当的载体和启动子； 2）必须在两个物种中进行疗效，安全性和毒性研究。我们已经在部分选择了适当的向量，开发了一种输送方法，并证明了概念研究的早期证明，显示了我们在我们的第1阶段应用中的功效。必须研究两种物种（一种啮齿动物和一种非岩体）以供FDA批准。希望通过检查这种新颖的分子性疗法，该公司将能够验证SERCA2A作为治疗靶点。在这里，我们建议进行所需的研究，以将我们定位为FDA要求的任何其他研究，这是在第三阶段资金结束时成功提交的研究新药应用所需的。