GENE THERAPY FOR HEMOPHILIA B

B 型血友病的基因治疗

• 批准号: 6351485
• 负责人: KOTOKU KURACHI
• 金额: $ 34.97万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6351485
• 关键词: SCID mouse; adeno associated virus group; antibody; coagulation factor IX; disease /disorder model; gene targeting; gene therapy; genetic transduction; genetically modified animals; hemophilia B; human tissue; immune tolerance /unresponsiveness; immunoregulation; laboratory rabbit; method development; muscle cells; myoblasts; recombinant proteins; tissue /cell culture; transfection; transfection /expression vector

Gene therapy studies, which began in the early 1980's, have now reached the point where critical importance of basic studies into the diseases and the biology associated with gene transfer have become widely acknowledged. In particular, studies on hemophilia B (factor IX deficiency) have greatly contributed to the understanding of gene transfer biology in general and have highlighted specific issues which must be systematically studied before safe and truly robust clinical human gene therapies can be developed. To date, most of these fundamental issues remain to be addressed. The studies detailed in this proposal will continue to focus study on hemophilia B by vigorously addressing selected critical issues and gaining insights into the basic biology underlying gene transfer. Studies proposed have three major aims centered on factor IX (FIX) as the model gene: Aim 1, delineation of the biology and mechanisms involved in muscle- targeted gene transfer; Aim 2, development of a robust FIX AAV (adeno-associated virus) - mediated gene transfer system; Aim 3, characterization of the immune responses to IX, delivered as a purified protein and by gene transfer approaches, and development of methods for induces immune tolerance. Establishment of an extensively studied and mechanistically well- understood gene therapy for hemophilia B will serve as a model for future gene therapy studies, and will provide an exciting foundation for development of clinical therapies, not only for hematological and metabolic diseases requiring systemic or local delivery of gene products, but also for other diseases such as muscular disorders.

基因治疗研究始于20世纪80年代初，现在已经达到了这样的程度，即对疾病和与基因转移相关的生物学的基础研究的关键重要性已经得到广泛承认。特别是，对血友病B（因子IX缺乏）的研究极大地促进了对基因转移生物学的理解，并突出了在开发安全和真正可靠的临床人类基因疗法之前必须系统研究的具体问题。迄今为止，这些基本问题中的大多数仍有待解决。本提案中详述的研究将继续通过大力解决选定的关键问题并深入了解基因转移的基础生物学，重点研究血友病B。以因子IX（FIX）为模型基因的研究主要有三个目的：目的1，阐明肌肉靶向基因转移的生物学和机制;目的2，开发一种稳定的FIX AAV（腺相关病毒）介导的基因转移系统;目的3，表征对作为纯化蛋白和通过基因转移方法递送的IX的免疫应答，以及开发诱导免疫耐受的方法。血友病B基因治疗的广泛研究和机制的充分理解的建立将作为未来基因治疗研究的模型，并将为临床治疗的开发提供令人兴奋的基础，不仅用于需要全身或局部递送基因产物的血液学和代谢疾病，而且用于其他疾病，如肌肉疾病。