Replacing bad (F)actors: hemophilia
Replacing bad (F)actors: hemophilia
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DOI：
10.1182/asheducation-2014.1.461
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发表时间：
2014-12-01
影响因子：
3
通讯作者：
Spencer, H. Trent
中科院分区：
文献类型：
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作者：
Doering, Christopher B.;Spencer, H. Trent
A 型血友病和 B 型血友病是由特定循环凝血因子（分别称为因子 VIII (FVIII) 和因子 IX (FIX)）功能缺陷引起的出血性疾病，其发病率为每 4000 名男性新生儿中就有 1 人发病。干细胞移植疗法有望治愈血友病，但目前可用的可移植干细胞产品无法实现内源性 FIX 或 FVIII 生物合成。因此，基于干细胞的血友病治疗方法主要集中在多能或多能干细胞的基因工程上。尽管多能干细胞被赋予了很高的期望和希望，但它们在临床实用性和安全性方面仍然缺乏特征。相比之下，成体谱系限制干细胞是临床设备中的既定药物。在临床建立的干细胞类型中，造血干细胞（HSC）使用最多，代表了几种遗传性和获得性疾病的护理标准。此外，HSC 是基因治疗应用的理想细胞载体，因为它们能够自我更新，重新填充整个血统，同时将转基因拷贝数放大 > 10(6) 倍，并且还可以直接进入血流。目前针对血友病 A 和 B 的 HSC 移植基因治疗方法的研究主要集中在以下方面：（1）确定安全有效的核酸转移方法，（2）优化转基因产物表达，（3）在维持 HSC 植入的同时最大限度地减少与调理方案相关的毒性，以及（4）克服先前存在的免疫力。根据现有数据和目前的进展速度，HSC移植基因治疗血友病的临床试验预计将在未来几年开始。
Hemophilia A and B are bleeding disorders that result from functional deficiencies in specific circulating blood clotting factors termed factor VIII (FVIII) and factor IX (FIX), respectively, and collectively display an incidence of 1 in 4000 male births. Stem cell transplantation therapies hold the promise of providing a cure for hemophilia, but currently available transplantable stem cell products do not confer endogenous FIX or FVIII biosynthesis. For this reason, stem cell-based approaches for hemophilia have focused primarily on genetic engineering of pluripotent or multipotent stem cells. While pluripotent stem cells have been branded with high expectation and promise, they remain poorly characterized in terms of clinical utility and safety. In contrast, adult-lineage-restricted stem cells are established agents in the clinical armamentarium. Of the clinically established stem cell types, hematopoietic stem cells (HSCs) are the most utilized and represent the standard of care for several genetic and acquired diseases. Furthermore, HSCs are ideal cellular vehicles for gene therapy applications because they self-renew, repopulate the entire blood lineage while concurrently amplifying the transgene copy number > 10(6) fold, and also have direct access to the bloodstream. Current research on HSC transplantation gene therapy approaches for hemophilia A and B is focused on the following: (1) identification of safe and efficient methods of nucleic acid transfer, (2) optimization of transgene product expression, (3) minimization of conditioning-regimen-related toxicity while maintaining HSC engraftment, and (4) overcoming preexisting immunity. Based on the existing data and current rate of progress, clinical trials of HSC transplantation gene therapy for hemophilia are predicted to begin in the coming years.