Laboratory of Molecular Virology, First Moscow State Medical University (Sechenov University), Moscow 119435, Russia.
Department of Biology and General Genetics, First Moscow State Medical University (Sechenov University), Moscow 105043, Russia.
Biomolecules. 2024 Jul 15;14(7):854. doi: 10.3390/biom14070854.
One of the well-known X-linked genetic disorders is hemophilia, which could be hemophilia A as a result of a mutation in the (factor VIII) gene or hemophilia B as a result of a mutation in the (factor IX) gene, leading to insufficient levels of the proteins essential for blood coagulation cascade. In patients with severe hemophilia, factor VIII or factor IX activities in the blood plasma are considerably low, estimated to be less than 1%. This is responsible for spontaneous or post-traumatic bleeding episodes, or both, leading to disease complications and death. Current treatment of hemophilia relies on the prevention of bleeding, which consists of expensive lifelong replacement infusion therapy of blood plasma clotting factors, their recombinant versions, or therapy with recombinant monoclonal antibodies. Recently emerged gene therapy approaches may be a potential game changer that could reshape the therapeutic outcomes of hemophilia A or B using a one-off vector in vivo delivery and aim to achieve long-term endogenous expression of factor VIII or IX. This review examines both traditional approaches to the treatment of hemophilia and modern methods, primarily focusing on gene therapy, to update knowledge in this area. Recent technological advances and gene therapeutics in the pipeline are critically reviewed and summarized. We consider gene therapy to be the most promising method as it may overcome the problems associated with more traditional treatments, such as the need for constant and expensive infusions and the presence of an immune response to the antibody drugs used to treat hemophilia.
一种著名的 X 连锁遗传疾病是血友病，其可能是由于 （VIII 因子）基因中的突变导致的血友病 A，或者是由于 （IX 因子）基因中的突变导致的血友病 B，导致血液凝固级联反应所必需的蛋白质水平不足。在严重血友病患者中，血浆中的 VIII 因子或 IX 因子活性显著降低，估计低于 1%。这导致自发性或创伤后出血发作，或两者兼而有之，导致疾病并发症和死亡。目前血友病的治疗依赖于预防出血，包括昂贵的终身替代输注疗法，即血浆凝血因子、其重组版本或重组单克隆抗体治疗。最近出现的基因治疗方法可能是一种潜在的改变游戏规则的方法，它可以使用一次性载体在体内传递，旨在实现 VIII 因子或 IX 的长期内源性表达，从而改变血友病 A 或 B 的治疗结果。本文回顾了治疗血友病的传统方法和现代方法，主要侧重于基因治疗，以更新该领域的知识。本文还批判性地审查和总结了最近的技术进步和基因治疗药物研发管线。我们认为基因治疗是最有前途的方法，因为它可能克服与更传统治疗方法相关的问题，例如对用于治疗血友病的抗体药物进行持续和昂贵的输注以及对其产生免疫反应的需要。
