Department of Orthopaedic Surgery, La Paz University Hospital, Madrid, Spain.
Curr Gene Ther. 2018;18(2):107-114. doi: 10.2174/1566523218666180214162312.
Several methods have been investigated to effectively and safely transmit genes that stimulate cells to release therapeutic factor VIII (FVIII) and factor IX (FIX) into the circulation of people with hemophilia (PWH).
To review the role of gene therapy (GT) in PWH.
A Cochrane Library and PubMed (MEDLINE) search related to the role of GT in hemophilia was analyzed.
The most promising vectors for hemophilia GT are adeno-associated virus (AAV) and lentivirus. Several gene methods are available to lessen risks related to random vector integration and insertional mutagenesis, based on designer nucleases or CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated system). However, off-target issues need to be more meticulously and widely evaluated. Some clinical studies on hemophilia B based on AAV have obtained transitory or subtherapeutic levels of FIX expression. Another problem is possible transitory liver toxicity. Therefore, to reduce unintentional immune responses, transitory immunosuppression must be used, particularly when administering high-vector doses. Codon-optimized FVIII or FIX transgenes are able to promote clotting factor expression levels. The inclusion of a hyper-active gain-of-function R338L mutation in the FIX gene (FIX-R338L [FIX Padua]) makes the procedure more effective.
Achieving a safe and efficient remedy for hemophilia A and B by means of GT vector engineering needs further improvement. No randomized or quasi-randomized clinical trials of GT for hemophilia have been found. Given it is in its incipient period, there is need for well-designed clinical trials to evaluate the long-term practicability, efficacy and risks of GT for PWH.
为了将能够刺激细胞释放治疗性凝血因子 VIII（FVIII）和凝血因子 IX（FIX）的基因有效且安全地输送到血友病患者（PWH）的循环系统中，人们已经研究了多种方法。
综述基因疗法（GT）在血友病中的作用。
对与 GT 在血友病中的作用相关的 Cochrane 图书馆和 PubMed（MEDLINE）检索进行分析。
腺相关病毒（AAV）和慢病毒是最有前途的血友病 GT 载体。基于设计型核酸酶或 CRISPR/Cas9（成簇规律间隔短回文重复/CRISPR 相关系统），有几种基因方法可降低与随机载体整合和插入突变相关的风险。然而，需要更仔细和广泛地评估脱靶问题。一些基于 AAV 的血友病 B 的临床研究获得了短暂或亚治疗水平的 FIX 表达。另一个问题是可能出现短暂的肝毒性。因此，为了减少非预期的免疫反应，必须使用短暂的免疫抑制，尤其是在给予高载体剂量时。密码子优化的 FVIII 或 FIX 转基因能够提高凝血因子表达水平。在 FIX 基因中加入一个高活性的功能获得性 R338L 突变（FIX-R338L [FIX Padua]）可使该程序更有效。
通过 GT 载体工程实现血友病 A 和 B 的安全有效治疗还需要进一步改进。尚未发现 GT 治疗血友病的随机或准随机临床试验。鉴于 GT 处于初期阶段，需要精心设计临床试验来评估 GT 对 PWH 的长期实用性、疗效和风险。
