GENE THERAPY FOR HEMOPHILIA B

基因治疗研究始于20世纪80年代初，现在已经达到了这样一种程度，即对与基因转移有关的疾病和生物学进行基础研究的重要性已得到广泛承认。特别是，对血友病B（因子IX缺乏症）的研究极大地促进了对基因转移生物学的总体理解，并突出了在开发安全和真正强大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。本提案中详细的研究将继续专注于血友病B的研究，大力解决选定的关键问题，并深入了解基因转移的基本生物学基础。以因子IX （FIX）作为模型基因为中心的研究主要有三个目标：目标1，描述肌肉靶向基因转移的生物学和机制；目标2：建立一个强大的FIX AAV（腺相关病毒）介导的基因转移系统；目标3：通过纯化蛋白和基因转移方法对IX的免疫反应进行表征，并开发诱导免疫耐受的方法。对血友病B的基因治疗进行广泛研究和机制上的充分理解，将为未来的基因治疗研究提供一个模型，并将为临床治疗的发展提供一个令人兴奋的基础，不仅对需要全身或局部传递基因产物的血液学和代谢性疾病，而且对其他疾病，如肌肉疾病。

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.