1] Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA [2] Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin 53226, USA [3] MACC Fund Research Center, Milwaukee, Wisconsin 53226, USA.
Nat Commun. 2013;4:2773. doi: 10.1038/ncomms3773.
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.
对于控制出血性疾病患者的过度出血，改善治疗方法至关重要。由于激活的血小板介导了对血管损伤的主要反应，我们假设凝血因子 VIII 在血小板内的储存可能为维持血友病 A 的止血提供一种局部诱导的治疗方法。在这里，我们表明造血干细胞基因治疗可以在移植后至少 2.5 年内预防血友病 A 犬发生严重出血事件。我们采用了一种基于慢病毒载体的临床相关策略，该载体编码 ITGA2B 基因启动子，该启动子驱动人 FVIII 的血小板特异性表达，允许 FVIII 从激活的血小板中储存和释放。一只动物接受 FVIII 与 von Willebrand 因子前肽-D2 结构域融合的杂交分子，该结构域可更有效地将 FVIII 转运到α-颗粒中。对血小板衍生的 FVIII 没有抑制性抗体表明，这种方法可能对拒绝 FVIII 替代治疗的患者有益。因此，血小板 FVIII 可能为血友病 A 患者提供有效的长期出血控制。
Zotero 插件
