Gene therapy for PIDs: progress, pitfalls and prospects.
Gene therapy for PIDs: progress, pitfalls and prospects.
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DOI：
10.1016/j.gene.2013.03.098
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发表时间：
2013-08-10
期刊：
影响因子：
3.5
通讯作者：
Thrasher AJ
中科院分区：
文献类型：
--
作者：
Mukherjee S;Thrasher AJ
过去十年，基因疗法在治疗多种原发性免疫缺陷病（PID）方面取得了实质性进展。目前的方法是通过病毒载体将治疗性转基因离体转移到患者来源的自体造血干细胞（HSC），然后在经过或不经过预处理的情况下移植回患者体内。针对不同 PID 的所有临床试验的总体结果非常令人鼓舞，但并非没有警告。插入诱变产生的恶性结果在与这些试验相关的不良事件中表现突出，并需要进行深入的临床前研究来确定不同病毒载体基因组整合的倾向。再加上与转基因表达有关的问题，在确定基因治疗方法的安全性、稳定性和有效性方面，治疗领域已经发生了范式转变。在这篇综述中，我们旨在总结针对 ADA-SCID、SCID-X1、CGD 和 WAS 的基因治疗试验所取得的进展，回顾其中的缺陷，并概述最近的进展，这些进展预计将进一步提高未来基因治疗方法的有利风险收益比。在缺乏合适供体的情况下，PID 基因治疗是 HSCT 的一种有前途的替代方案。针对各种PID的基因治疗临床试验已显示出显着的疗效。逆转录病毒和慢病毒载体是目前基因递送的支柱。插入诱变和载体沉默是主要关注点。目前正在研究和验证新的基因传递方法。
Substantial progress has been made in the past decade in treating several primary immunodeficiency disorders (PIDs) with gene therapy. Current approaches are based on ex-vivo transfer of therapeutic transgene via viral vectors to patient-derived autologous hematopoietic stem cells (HSCs) followed by transplantation back to the patient with or without conditioning. The overall outcome from all the clinical trials targeting different PIDs has been extremely encouraging but not without caveats. Malignant outcomes from insertional mutagenesis have featured prominently in the adverse events associated with these trials and have warranted intense pre-clinical investigation into defining the tendencies of different viral vectors for genomic integration. Coupled with issues pertaining to transgene expression, the therapeutic landscape has undergone a paradigm shift in determining safety, stability and efficacy of gene therapy approaches. In this review, we aim to summarize the progress made in the gene therapy trials targeting ADA-SCID, SCID-X1, CGD and WAS, review the pitfalls, and outline the recent advancements which are expected to further enhance favourable risk benefit ratios for gene therapeutic approaches in the future. PID gene therapy is a promising alternative to HSCT in absence of suitable donors. Gene therapy clinical trials targeting various PIDs have shown significant efficacy. Retroviral and lentiviral vectors are presently the mainstay of gene delivery. Insertional mutagenesis and vector silencing constitute the main concerns. Novel gene delivery approaches are currently being investigated and validated.
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