Keating A, Nolan E, Filshie R, Dev S B
University of Toronto Autologous Blood and Marrow Transplant Program, The Toronto Hospital, Toronto, Ontario, Canada.
Methods Mol Med. 2000;37:359-68. doi: 10.1385/1-59259-080-2:359.
Hemophilia B is an X-linked genetic disorder that typically results from chronic circulating deficiency of blood coagulation factor IX (FIX) (1). While the occurrence of hemophilia B is significantly less frequent than hemophilia A (factor VIII, deficiency) it has received special attention as a model for gene therapy. This is because hemophilia B is one of the least complicated genetic diseases from the point of view of demonstrating the proof of principle of a gene therapy protocol. Specifically, hemophilia B is a single gene recessive disorder and a wide range of tissues can be targeted for FIX gene delivery and strict regulation of FIX expression is not required. In addition, the 2.8 kb FIX cDNA is much smaller than the 9 kb FVIII cDNA, and FIX expression in transfected mammalian cells has been less problematic than FVIII expression (2). Since clinical severity of bleeding episodes closely corresponds to a patient's FIX activity, achieving even partial restoration of normal FIX levels in the bloodstream can alleviate internal bleeding. Individuals with FIX levels less than 1% of normal experience severe symptomatic episodes but providing roughly 5% of normal levels (i.e., 250 ng/mL plasma) can significantly reduce the frequency and severity of bleeding episodes and reduce long term complications (3). Treatment of hemophilia B primarily relies on intravenous injections of FIX protein purified from pooled human plasma, or very recently, on newly developed recombinant FIX. Treatment is applied typically only when bleeding episodes have occurred or are expected, for example, in case of a trauma or surgery. Although the risk of viral transmission of HIV and hepatitis viruses has been largely eliminated the absolute safety of any product derived from blood cannot be guaranteed. Furthermore, supplies of factor concentrates are limited and costs (especially if prophylactic treatment is being considered) are high. Thus, the application of gene therapy to hemophilia, whereby long-term correction of factor IX deficiency might be achieved, would be extremely useful.
血友病B是一种X连锁遗传病，通常由血液凝固因子IX（FIX）长期循环缺乏引起（1）。虽然血友病B的发病率明显低于血友病A（因子VIII缺乏），但作为基因治疗的模型，它受到了特别关注。这是因为从证明基因治疗方案的原理的角度来看，血友病B是最不复杂的遗传病之一。具体而言，血友病B是一种单基因隐性疾病，可以将多种组织作为FIX基因递送的靶点，并且不需要严格调控FIX的表达。此外，2.8 kb的FIX cDNA比9 kb的FVIII cDNA小得多，并且在转染的哺乳动物细胞中，FIX的表达比FVIII的表达问题更少（2）。由于出血发作的临床严重程度与患者的FIX活性密切相关，即使在血液中实现正常FIX水平的部分恢复也可以减轻内出血。FIX水平低于正常水平1%的个体经历严重的症状性发作，但提供大约5%的正常水平（即250 ng/mL血浆）可以显著降低出血发作的频率和严重程度，并减少长期并发症（3）。血友病B的治疗主要依赖于静脉注射从混合人血浆中纯化的FIX蛋白，或者最近依赖于新开发的重组FIX。通常仅在出血发作已经发生或预期会发生时进行治疗，例如在创伤或手术的情况下。尽管HIV和肝炎病毒的病毒传播风险已基本消除，但不能保证任何血液衍生产品的绝对安全性。此外，凝血因子浓缩物的供应有限且成本高昂（特别是如果考虑预防性治疗）。因此，将基因治疗应用于血友病，从而可能实现因子IX缺乏的长期纠正，将非常有用。
