NOVEL METHODS OF GENE THERAPY FOR LIVER DISEASE

肝病基因治疗的新方法

• 批准号: 2838010
• 负责人: TIMOTHY J DAVERN
• 金额: $ 11.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-19 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2838010
• 关键词: Adenoviridae; Retroviridae; antibody specificity; antireceptor antibody; cell line; chimeric proteins; gene expression; gene therapy; genetic transduction; histology; immunogenetics; immunomodulators; inflammation; laboratory rabbit; liver cells; liver disorder; low density lipoprotein receptor; protein engineering; recombinant virus; reporter genes; transfection; transfection /expression vector; virus envelope

DESCRIPTION (taken from application) The candidate is currently a Clinical Instructor in Medicine and a Fellow in the UCSF Molecular Medicine Training Program. His long-term career goal is to become a productive biomedical investigator with an independent research program focused on the development of novel and clinically-applicable gene delivery systems for hepatic gene therapy. Towards this goal, the candidate has developed, along with his Research Mentor, Dr. Y.W. Kan, a structured career development program that incorporates a supervised research curriculum as well as graduate course work and specialized workshops. The candidate's research proposal explores two novel strategies for hepatic gene delivery, one based on retroviral vectors and the other on adenoviral vectors. The ability to efficiently and selectively deliver therapeutic genes to hepatocytes in vivo would represent a major advance in the treatment of both hereditary and acquired diseases of the liver. Unfortunately, none of the delivery systems currently available results in expression which is liver-specific, efficient and long-lasting. Gene delivery via retroviral vectors, the strategy most commonly employed in clinical trials, results in stable integration of genes, thus permitting long-lasting expression, but the current generation of retroviral vectors is neither targeted nor efficient. The candidate plans to design, engineer, and test retroviral vectors that are both efficient and hepatocyte-specific as part of the research plan. His hypothesis, which is based conceptually on extensive work done in the laboratory of the mentor, is that specific targeting and enhanced efficiency of retroviral vectors can be achieved through the purposeful manipulation of ligand-receptor interactions. In order to test this hypothesis, the candidate plans to redirect the tissue tropism of retroviral vectors by engineering into their envelope proteins ligands that bind specifically to receptors on hepatocytes. In studies complementary to these, the candidate will also test whether focused immunomodulation using a recombinant fusion protein, CTLA4Ig, that he has designed and constructed will specifically subvert the destructive immune responses that thwart adenoviral gene delivery. These studies, performed in an outstanding research environment as part of a structured career development program, will provide the technical research skills, theories and conceptualizations that the candidate will need to launch an career as an independent investigator.

DESCRIPTION (taken from application) The candidate is currently a Clinical Instructor in Medicine and a Fellow in the UCSF Molecular Medicine Training Program. His long-term career goal is to become a productive biomedical investigator with an independent research program focused on the development of novel and clinically-applicable gene delivery systems for hepatic gene therapy. Towards this goal, the candidate 与他的研究导师Y.W.一起发展了Kan，一个结构化 纳入监督研究的职业发展计划 课程以及研究生课程工作和专业研讨会。 这 候选人的研究建议探讨了肝基因的两种新颖策略 分娩，一种基于逆转录病毒载体，另一个基于腺病毒 向量。 有效，有选择地提供治疗的能力 体内肝细胞的基因将代表 治疗肝脏的遗传性和获得性疾病。 不幸的是，当前没有一个可用的交付系统会导致 表达是肝特异性，有效且持久的表达。 基因 通过逆转录病毒载体交付，最常用的策略 临床试验，导致基因整合，因此允许 持久的表达，但是当前的逆转录病毒载体是 既不是针对性也不有效的。 候选人计划设计，工程师， 和测试逆转录病毒载体，既有效率又是肝细胞特异性的 作为研究计划的一部分。 他的假设是基于概念的 在指导者实验室所做的大量工作中， 可以实现逆行病毒载体的靶向和提高效率 通过有目的的操纵配体 - 受体相互作用。 在 为了检验这一假设，候选人计划重定向组织 逆转录病毒载体的向向主义通过工程化到信封蛋白 特异性与肝细胞上受体结合的配体。 在研究中 互补的，候选人还将测试是否集中 使用重组融合蛋白CTLA4IG的免疫调节，他的具有 设计和构造将特别颠覆破坏性的免疫 挫败腺病毒基因递送的反应。 这些研究在 作为结构化职业的一部分的杰出研究环境 开发计划将提供技术研究技能，理论 以及候选人将需要发起职业的概念化 独立研究者。