Gene therapy for hemophilia
Gene therapy for hemophilia
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DOI：
10.1182/hematology.2019000007
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发表时间：
2019-12-01
影响因子：
3
通讯作者：
Nathwani, Amit C.
中科院分区：
文献类型：
--
作者：
Nathwani, Amit C.
基因治疗提供了治愈血友病患者的可能性，通过在转移功能基因以取代血友病患者自身的缺陷基因后建立因子VIII或因子IX（FIX）的连续内源性表达。血友病患者非常适合基因治疗，因为血液因子水平的小幅增加（>=正常值的5%）与严重受影响患者的出血表型的显着改善相关。2011年，St. Jude/UCL I/II期试验首次提供了明确证据，证明重度血友病B患者接受腺相关病毒（AAV）载体单次给药后FIX水平呈剂量依赖性稳定升高。在7年随访期内，高剂量队列中转基因FIX表达保持稳定，接近正常值的5%，导致自发性出血和FIX蛋白使用大幅减少，无毒性。这项研究之后，在血友病A和B的基因治疗方面取得了无与伦比的进展，导致凝血因子活性接近正常或接近正常水平，这与单次施用AAV载体后先前严重受影响的患者的“零出血率”相关。因此，AAV基因疗法可能改变血友病A和B的治疗模式。这篇综述探讨了最近的进展和剩余的局限性，需要克服更广泛的可用性，这种新的治疗遗传性出血性疾病。
Gene therapy offers the potential for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX (FIX) following transfer of a functional gene to replace the hemophilic patient's own defective gene. The hemophilias are ideally suited for gene therapy because a small increment in blood factor levels (>= 5% of normal) is associated with significant amelioration of bleeding phenotype in severely affected patients. In 2011, the St. Jude/UCL phase 1/2 trial was the first to provide clear evidence of a stable dose-dependent increase in FIX levels in patients with severe hemophilia B following a single administration of adeno-associated viral (AAV) vectors. Transgenic FIX expression has remained stable at similar to 5% of normal in the high-dose cohort over a 7-year follow-up period, resulting in a substantial reduction in spontaneous bleeding and FIX protein usage without toxicity. This study has been followed by unparalleled advances in gene therapy for hemophilia A and B, leading to clotting factor activity approaching normal or near-normal levels associated with a "zero bleed rates" in previously severely affected patients following a single administration of AAV vectors. Thus, AAV gene therapies are likely to alter the treatment paradigm for hemophilia A and B. This review explores recent progress and the remaining limitations that need to be overcome for wider availability of this novel treatment of inherited bleeding disorders.