Gene Therapy for Hemophilia - From Basic Science to First Approvals of "One-and-Done" Therapies.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Roland W Herzog, Radoslaw Kaczmarek, Katherine A High
{"title":"Gene Therapy for Hemophilia - From Basic Science to First Approvals of \"One-and-Done\" Therapies.","authors":"Roland W Herzog, Radoslaw Kaczmarek, Katherine A High","doi":"10.1016/j.ymthe.2025.03.043","DOIUrl":null,"url":null,"abstract":"<p><p>Realistic paths to gene therapy for the X-linked bleeding disorder hemophilia started to materialize in the mid 1990s, resulting in disease correction in small and large animal models. Out of a diversity of approaches, in vivo adeno-associated viral (AAV) gene transfer to hepatocytes emerged as the most promising strategy, eventually forming the basis for multiple advanced clinical trials and regulatory approval of two products for the treatment of hemophilia B (coagulation factor IX deficiency) and one for hemophilia A (factor VIII deficiency). Ideally, gene therapy is effective with a single administration, thus providing therapeutic factor levels over a period of years, without the need for frequent injections. Overcoming multiple obstacles, some not predicted by pre-clinical studies, sustained partial to complete correction of coagulation for several years to an entire decade has now been documented in patients, with observation ongoing. A hyperactive form of FIX improved efficacy in hemophilia B, and superior engineered variants of FVIII are emerging. Nonetheless, challenges remain, including pre-existing immunity to AAV capsids, toxicities, inter-patient variability in response to treatment, and difficulty in obtaining durable therapeutic expression of FVIII. In alternative approaches, in vivo gene editing and ex vivo gene therapies targeting hemopoietic cells are in development.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1000,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2025.03.043","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Realistic paths to gene therapy for the X-linked bleeding disorder hemophilia started to materialize in the mid 1990s, resulting in disease correction in small and large animal models. Out of a diversity of approaches, in vivo adeno-associated viral (AAV) gene transfer to hepatocytes emerged as the most promising strategy, eventually forming the basis for multiple advanced clinical trials and regulatory approval of two products for the treatment of hemophilia B (coagulation factor IX deficiency) and one for hemophilia A (factor VIII deficiency). Ideally, gene therapy is effective with a single administration, thus providing therapeutic factor levels over a period of years, without the need for frequent injections. Overcoming multiple obstacles, some not predicted by pre-clinical studies, sustained partial to complete correction of coagulation for several years to an entire decade has now been documented in patients, with observation ongoing. A hyperactive form of FIX improved efficacy in hemophilia B, and superior engineered variants of FVIII are emerging. Nonetheless, challenges remain, including pre-existing immunity to AAV capsids, toxicities, inter-patient variability in response to treatment, and difficulty in obtaining durable therapeutic expression of FVIII. In alternative approaches, in vivo gene editing and ex vivo gene therapies targeting hemopoietic cells are in development.

血友病的基因治疗-从基础科学到“一次性”疗法的首次批准。
基因治疗x连锁出血性疾病血友病的现实途径在20世纪90年代中期开始实现,导致小型和大型动物模型的疾病纠正。在多种方法中,体内腺相关病毒(AAV)基因转移到肝细胞是最有希望的策略,最终形成了多个高级临床试验的基础,并批准了两种治疗血友病B(凝血因子IX缺乏症)和一种治疗血友病a(凝血因子VIII缺乏症)的产品。理想情况下,基因治疗只需一次给药即可有效,从而在数年内提供治疗因子水平,而无需频繁注射。克服了多种障碍,有些是临床前研究没有预测到的,持续几年到整整十年的部分到完全的凝血纠正现在已经在患者中得到了记录,观察正在进行中。FIX的一种多活性形式提高了对B型血友病的疗效,并且FVIII的优良工程变体正在出现。尽管如此,挑战仍然存在,包括对AAV衣壳的预先免疫,毒性,患者对治疗反应的差异,以及难以获得持久的治疗性FVIII表达。在替代方法中,针对造血细胞的体内基因编辑和体外基因治疗正在开发中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信