Abstract

Hemophilia is a congenital hemorrhagic disease caused by genetic abnormalities in coagulation factor VIII or factor IX. Current conventional therapy to prevent bleeding requires frequent intravenous injections of coagulation factor concentrates from early childhood. Accordingly, gene therapy for hemophilia remains an exciting future prospect for patients and their families, due to its potential to cure the disease through a one-time treatment. After a series of successes in basic research, recent clinical trials have demonstrated clear efficacy of gene therapy for hemophilia using adeno-associated virus (AAV) vectors. Although this is likely to alter the paradigm of hemophilia care in the near future, it will be important to overcome immune responses against AAV. Gene therapy for hemophilia cannot be given to patients with anti-AAV capsid-neutralizing antibodies, and cellular immunity with CD8⁺ T cells should be controlled for sustained expression. Furthermore, long-term therapeutic effects should be closely observed because of the failure of the AAV vector genome to replicate during cell division. This review focuses on the basis of gene therapy, current successes of clinical trials, and the future direction of hemophilia gene therapy.

中文翻译：

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血友病基因治疗的进展：基础，现状和未来展望

摘要

血友病是由凝血因子VIII或IX的遗传异常引起的先天性出血性疾病。当前防止出血的常规疗法需要从童年时代开始频繁静脉内注射凝血因子浓缩物。因此，由于血友病可以通过一次性治疗治愈疾病，因此对血友病的基因治疗仍将为患者及其家人带来令人振奋的未来前景。在基础研究中取得了一系列成功之后，最近的临床试验证明了使用腺相关病毒（AAV）载体对血友病进行基因治疗的明确功效。尽管这可能会在不久的将来改变血友病治疗的范式，但克服针对AAV的免疫反应将非常重要。⁺ T细胞应被控制以持续表达。此外，由于AAV载体基因组在细胞分裂过程中无法复制，因此应密切观察长期治疗效果。这篇综述着重于基因治疗的基础，临床试验的当前成功以及血友病基因治疗的未来方向。