Vector Identification and Gene Delivery Approach in Pigs

猪的载体鉴定和基因传递方法

• 批准号: 7177706
• 负责人: Judith K Gwathmey
• 金额: $ 145.79万
• 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/7177706
• 关键词: Address; Arrhythmia; Automobile Driving; Bacteria; Blood Chemical Analysis; CMV promoter; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cause of Death; Clinical; Defect; Devices; Dose; Family suidae; Funding; Gene Delivery; Gene Transfer; Genes; Genetic; Heart; Heart Contractilities; Heart failure; Human; Hypertrophy; In Vitro; Investigational New Drug Application; Ischemia; Left Ventricular Function; Left Ventricular Remodeling; Lesion; Long-Term Effects; Mammalian Cell; Mechanics; Methods; Modeling; Molecular; Morbidity - disease rate; Muscle Cells; Myocardial Ischemia; Myocardial Revascularization; Numbers; Patients; Phase; Plasma; Positioning Attribute; Property; Protein Overexpression; Quality of life; Rattus; Relaxation; Rodent; Rodent Model; SERCA2a; Safety; Sarcoplasmic Reticulum; Sus scrofa; Testing; Therapeutic; Tissues; Toxic effect; Transfection; Transgenes; Transplantation; Troponin T; United States Food and Drug Administration; Ventricular Remodeling; Viral Vector; adeno-associated viral vector; concept; gene therapy; genotoxicity; hemodynamics; improved; in vivo; mortality; novel; particle; pressure; promoter; restoration; therapeutic target; uptake; vector

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取得了进步，包括药物治疗、心肌血运重建术、机械辅助装置和移植，但心力衰竭仍然是世界范围内死亡的主要原因。因此，一种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尤其具有吸引力。