Monahan Paul E
Gene Therapy Center, Department of Pediatrics, and Harold R. Roberts Comprehensive Hemophilia Diagnostic and Treatment Center, University of North Carolina, Chapel Hill, NC.
Hematology Am Soc Hematol Educ Program. 2015;2015:33-40. doi: 10.1182/asheducation-2015.1.33.
For more than 3 decades, the scientific community has pursued gene correction of hemophilia, with the goal that an individual with congenitally deficient factor VIII or factor IX might synthesize adequate endogenous clotting factor to be relieved of burdensome repeated clotting factor infusions, as well as the emotional weight of continuous hemorrhage risk. Recent reports of successful factor IX gene therapy and partial correction of the bleeding phenotype have raised the bar for success for a robust crop of new clinical gene therapy efforts for both hemophilia A and B. At the same time that gene therapy is gaining momentum, suggesting the possibility of relief from regular intravenous coagulation protein replacement, a number of innovative technologies that enhance hemostatic potential independently of replacement factor administration are demonstrating success in human clinical application. Human clinical trial progress is reviewed regarding a recombinant bispecific IgG antibody to factors IXa and X that mimics factor VIII cofactor activity, as well as monoclonal antibody and short interfering RNA strategies that demonstrate hemostatic efficacy via opposing inhibitors of coagulation. These strategies, associated with prolonged hemostatic potential following subcutaneous (ACE910, ALN-AT3, Concizumab) or single administration (eg, gene therapy) make it possible to imagine a day when recombinant clotting factor administration, rather than being a daily preoccupation, is relegated to an adjunctive role in supporting more novel standard of care therapies.
三十多年来，科学界一直致力于血友病的基因校正，目标是让先天性缺乏凝血因子VIII或凝血因子IX的个体能够合成足够的内源性凝血因子，从而摆脱繁重的反复凝血因子输注负担，以及持续出血风险带来的心理压力。最近关于成功进行凝血因子IX基因治疗和部分纠正出血表型的报道，提高了针对血友病A和B的一系列新的临床基因治疗努力的成功标准。与此同时，基因治疗正蓄势待发，这意味着有可能不再需要定期静脉注射凝血蛋白替代物，一些独立于替代因子给药而增强止血潜力的创新技术正在人类临床应用中取得成功。本文综述了一种模拟凝血因子VIII辅因子活性的重组双特异性IgG抗体（针对凝血因子IXa和X）以及通过对抗凝血抑制剂来证明止血疗效的单克隆抗体和短干扰RNA策略在人体临床试验中的进展。这些策略，与皮下注射（ACE910、ALN-AT3、Conizumab）或单次给药（如基因治疗）后延长的止血潜力相关，使得人们可以设想有一天，重组凝血因子给药不再是日常的主要事务，而是在支持更新颖的标准治疗方法中发挥辅助作用。
