Practical Implications of Factor IX Gene Transfer for Individuals with Hemophilia B: A Clinical Perspective
Practical Implications of Factor IX Gene Transfer for Individuals with Hemophilia B: A Clinical Perspective
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DOI：
10.1089/humc.2017.253
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发表时间：
2018-06-01
影响因子：
--
通讯作者：
Sawyer, Eileen K.
中科院分区：
文献类型：
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作者：
Miesbach, Wolfgang;Sawyer, Eileen K.
重度血友病的基因治疗即将进入临床实践。然而，鉴于基因转移是一项相对较新的技术，在这一领域的临床经验有限。因此，这篇临床视角的文章将回顾支持该领域基因治疗的证据，探讨在临床环境中与患者进行基因治疗对话的方法，并介绍最近血友病基因治疗临床试验的一位参与者的病例。使用腺相关病毒（AAV）载体转移功能因子IX （FIX）在血友病中的临床试验报告了FIX活性增加到功能水平，出血频率降低，并且减少或取消了昂贵的FIX替代需求。aav介导的基因治疗的安全性也似乎是积极的，肝酶可控制的无症状增加是最常见的不良事件。更仔细地检查一个血友病B临床病例，基因转移将治疗前的6例（未知或自发）出血减少到治疗后的3例（自发）出血，同时FIX置换减少55%。参与者在治疗后经历了创伤性出血的增加，这似乎反映了增加的身体活动和早期停止预防。在基因转移后，参与者认为他的血友病被“治愈”了，这强调了管理患者期望的必要性，特别是在治疗后的即时活动水平和出血风险方面。血友病的基因治疗有可能改变受影响个体的生活，并有可能创造一个新的血友病患者类别，他们已经从严重表型转变为轻度表型。尽管具有轻度表型，但这些个体可能保留了严重血友病多年出血风险增加和关节损伤的遗产，与更典型的轻度血友病个体相比，需要不同的临床管理。
Gene therapy for severe hemophilia is on the cusp of entering clinical practice. However, there is limited clinical experience in this area given that gene transfer is a relatively recent technology. Therefore, this clinical perspective article will review the evidence supporting gene therapy in this field, examine ways to open a dialogue about gene therapy with patients in the clinic setting, and present a case of a participant in a recent clinical trial of gene therapy for hemophilia. Clinical trials in hemophilia using adeno-associated virus (AAV) vectors to transfer functional factor IX (FIX) have reported increases in FIX activity to functional levels, reduced bleed frequency, and a lessening or abrogation of the need for costly FIX replacement. The safety profile of AAV-mediated gene therapy also appears positive, with manageable, asymptomatic increases in liver enzymes being the most commonly described adverse event. Examining a clinical case in hemophilia B more closely, gene transfer decreased annualized bleeds from six (unknown or spontaneous) bleeds before treatment to three (spontaneous) bleeds after treatment alongside a 55% reduction in FIX replacement. The participant experienced an increase in traumatic bleeds after treatment, which appears to reflect increased physical activity and early prophylaxis discontinuation. After the gene transfer, the participant considered his hemophilia to be "cured," which emphasizes the need to manage patient expectations, particularly regarding activity levels and bleed risk in the immediate post-treatment period. Gene therapy for hemophilia has the potential to transform the lives of affected individuals and is likely to create a new class of hemophilia patient who has shifted from a severe to a mild phenotype. Despite having a mild phenotype, these individuals may retain a legacy of increased bleed risk and joint damage from their years with severe hemophilia and will need different clinical management compared to a more typical individual with mild hemophilia.