Margaritis Paris
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Front Biosci (Schol Ed). 2012 Jan 1;4(1):287-99. doi: 10.2741/s269.
Qualitative or quantitative defects in the genes for coagulation factors VIII (FVIII) or IX (FIX) result in a life-threatening, bleeding phenotype (hemophilia A (HA) or B (HB), respectively). Although hemophilia treatment by clotting factor replacement is effective, a proportion of patients develop neutralizing antibodies (inhibitors) to the infused factor that complicate the disease management. For inhibitor patients, recombinant human activated coagulation Factor VII (rhFVIIa), when administered at therapeutic doses, has been shown to bypass the deficiency in FVIII or FIX and result in hemostasis. As an alternative to this protein infusion therapy, a gene-based approach for the treatment of hemophilia with inhibitors has been developed, using continuous expression of a transgene coding for FVIIa following viral-mediated delivery. This approach was validated in hemophilic mice and, notably, in dogs as a model that closely resembles the human disease. In particular, liver-directed FVIIa gene delivery in hemophilic dogs resulted in multi-year transgene expression that ameliorated the bleeding phenotype, without thrombotic complications. These data support the gene-based FVIIa expression as a novel bypass therapy for hemophilia with inhibitors.
凝血因子VIII（FVIII）或IX（FIX）基因的定性或定量缺陷会导致危及生命的出血表型（分别为血友病A（HA）或B（HB））。尽管通过凝血因子替代疗法治疗血友病是有效的，但一部分患者会对注入的因子产生中和抗体（抑制剂），这使疾病管理变得复杂。对于有抑制剂的患者，重组人活化凝血因子VII（rhFVIIa）在以治疗剂量给药时，已被证明可以绕过FVIII或FIX的缺陷并实现止血。作为这种蛋白质输注疗法的替代方法，已经开发出一种基于基因的方法来治疗有抑制剂的血友病，即通过病毒介导的递送持续表达编码FVIIa的转基因。这种方法在血友病小鼠中得到了验证，值得注意的是，在与人类疾病非常相似的犬类模型中也得到了验证。特别是，在血友病犬中进行肝脏靶向FVIIa基因递送导致了多年的转基因表达，改善了出血表型，且无血栓形成并发症。这些数据支持基于基因的FVIIa表达作为一种治疗有抑制剂的血友病的新型旁路疗法。
