Coagulation Products Safety Supply and Access Committee, World Federation of Hemophilia, Montreal, Quebec, Canada.
Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Haemophilia. 2022 May;28 Suppl 4(Suppl 4):35-43. doi: 10.1111/hae.14530.
Haemophilia therapy has evolved from rudimentary transfusion-based approaches to an unprecedented level of innovation with glimmers of functional cure brought by gene therapy. After decades of misfires, gene therapy has normalized factor (F)VIII and factor (F)IX levels in some individuals in the long term. Several clinical programmes testing adeno-associated viral (AAV) vector gene therapy are approaching completion with imminent regulatory approvals.
Phase 3 studies along with multiyear follow-up in earlier phase investigations raised questions about efficacy as well as short- and long-term safety, prompting a reappraisal of AAV vector gene therapy. Liver toxicities, albeit mostly low-grade, occur in the first year in at least some individuals in all haemophilia A and B trials and are poorly understood. Extreme variability and unpredictability of outcome, as well as a slow decline in factor expression (seemingly unique to FVIII gene therapy), are vexing because immune responses to AAV vectors preclude repeat dosing, which could increase suboptimal or restore declining expression, while overexpression may result in phenotoxicity. The long-term safety will need lifelong monitoring because AAV vectors, contrary to conventional wisdom, integrate into chromosomes at the rate that calls for vigilance.
AAV transduction and transgene expression engage the host immune system, cellular DNA processing, transcription and translation machineries in ways that have been only cursorily studied in the clinic. Delineating those mechanisms will be key to finding mitigants and solutions to the remaining problems, and including individuals who cannot avail of gene therapy at this time.
血友病的治疗已经从基本的输血方法发展到了前所未有的创新水平，基因疗法带来了功能性治愈的曙光。经过几十年的失败，基因疗法已经在一些个体中长期实现了因子（F）VIII 和因子（F）IX 的正常水平。几个正在测试腺相关病毒（AAV）载体基因疗法的临床项目即将完成监管审批。
第 3 阶段研究以及早期阶段研究的多年随访对疗效以及短期和长期安全性提出了质疑，促使人们重新评估 AAV 载体基因疗法。肝脏毒性，尽管大多为低级别，在所有血友病 A 和 B 试验中，至少在某些个体的第一年就会发生，而且目前了解甚少。结果的极端可变性和不可预测性，以及因子表达的缓慢下降（似乎是 FVIII 基因治疗所独有的），令人感到困扰，因为 AAV 载体的免疫反应排除了重复给药，这可能会增加表达不理想或恢复下降的风险，而过度表达可能会导致表型毒性。由于 AAV 载体与传统观念相反，以需要警惕的速度整合到染色体中，因此需要终身监测长期安全性。
AAV 转导和转基因表达以在临床上仅粗略研究过的方式，涉及宿主免疫系统、细胞 DNA 处理、转录和翻译机制。阐明这些机制将是找到缓解剂和解决剩余问题的关键，包括目前无法接受基因治疗的个体。
