本期Nature Communications上发表的一篇论文报告说,患有出血性疾病“A型血友病”的狗采用基因疗法成功得到了治疗。这项研究(在其中患病的狗被发现2.5年时间没有发生严重出血)是第一次采用以血细胞为目标的基因疗法在一个大型动物模型中演示“A型血友病”的治疗,代表着朝在临床上对严重“A型血友病”人类患者采用这种疗法的方向上迈进了一步。
“A型血友病”(与凝血蛋白“因子VIII”缺乏相关的一种遗传性出血疾病)影响万分之一的人。David Wilcox及同事利用一种病毒将一个功能性“因子VIII”基因引入到患有“A型血友病”的狗的“外周血干细胞”内。这种基因疗法(该研究小组在三只狗身上对这种疗法的不同形式进行了测试)导致 “因子VIII”在血小板中的生成和存储,而这以前在这些动物身上是不可能发生的。作者报告说,在接受基因疗法后产生最高水平“因子VIII”的两只狗在整个2.5年的随访期没有发生过严重出血。三只实验狗(在基因疗法后接受免疫抑制剂用药长达90天)中没有一只产生针对“因子VIII”的抗体,而如果有这种抗体的话会影响治疗效果。(生物谷Bioon.com)
生物谷推荐的英文摘要
Nature Communications doi:10.1038/ncomms3773
Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A
Lily M. Du,Paquita Nurden,Alan T. Nurden,Timothy C. Nichols,Dwight A. Bellinger,Eric S. Jensen,Sandra L. Haberichter,Elizabeth Merricks,Robin A. Raymer,Juan Fang,Sevasti B. Koukouritaki,Paula M. Jacobi,Troy B. Hawkins,Kenneth Cornetta,Qizhen Shi& David A. Wilcox
It is essential to improve therapies for controlling excessive bleeding in patients with haemorrhagic disorders. As activated blood platelets mediate the primary response to vascular injury, we hypothesize that storage of coagulation Factor VIII within platelets may provide a locally inducible treatment to maintain haemostasis for haemophilia A. Here we show that haematopoietic stem cell gene therapy can prevent the occurrence of severe bleeding episodes in dogs with haemophilia A for at least 2.5 years after transplantation. We employ a clinically relevant strategy based on a lentiviral vector encoding the ITGA2B gene promoter, which drives platelet-specific expression of human FVIII permitting storage and release of FVIII from activated platelets. One animal receives a hybrid molecule of FVIII fused to the von Willebrand Factor propeptide-D2 domain that traffics FVIII more effectively into α-granules. The absence of inhibitory antibodies to platelet-derived FVIII indicates that this approach may have benefit in patients who reject FVIII replacement therapies. Thus, platelet FVIII may provide effective long-term control of bleeding in patients with haemophilia A.