RNAi and gene therapy: a mutual attraction.
RNAi and gene therapy: a mutual attraction.
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DOI：
10.1182/asheducation-2007.1.473
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
D. Grimm;M. Kay
中科院分区：
文献类型：
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作者：
D. Grimm;M. Kay
RNA干扰（RNAi）是一种遗传学上保守的细胞现象，是由小的双链RNA介导的基因表达的序列特异性转录后沉默，它为基础研究和药物开发带来了巨大的希望。从医学角度来看，特别有吸引力的是新的RNAi方法与已建立的基因转移策略的并列，特别是用于向患者有效和组织特异性RNAi递送的病毒载体。在这里，我们总结了基于RNAi的基因治疗方法的最新实验和临床进展。我们简要描述了新出现的非病毒策略的siRNA转移，比较目前主要开发的三种病毒载体作为shRNA运载工具，腺病毒，慢病毒，腺相关病毒（AAV）。此外，我们描述了临床上最相关的遗传，获得性或传染性目标正在追求的治疗目的。具体而言，我们评估了载体介导的RNAi用于治疗病毒过程、实体癌、淋巴增生性疾病以及神经退行性疾病和眼部疾病的用途。此外，我们强调进一步新兴的应用，包括干细胞疗法和动物转基因，以及讨论一些潜在的陷阱和固有的个别方法的局限性。虽然我们预测，最终的方案将通过我们对人类RNAi生物学复杂性的不断了解以及对病毒穿梭设计的不断改进而形成，但RNAi和基因治疗成功结合的潜在科学和医学利益似乎是巨大的。
The phylogenetically conserved cellular phenomenon of RNA interference (RNAi)-the sequence-specific post-transcriptional silencing of gene expression mediated by small double-stranded RNAs-holds substantial promise for basic research and for drug development. Particularly attractive from a medical standpoint is the juxtaposition of new RNAi methodology with established gene transfer strategies, especially viral vectors for efficient and tissue-specific RNAi delivery to patients. Here, we summarize the latest experimental and clinical advances in RNAi-based gene therapy approaches. We briefly portray emerging nonviral strategies for siRNA transfer, before comparing the three viral vectors currently predominantly developed as shRNA delivery vehicles, adenovirus, lentivirus, and adeno-associated virus (AAV). Moreover, we describe the most clinically relevant genetic, acquired or infectious targets being pursued for therapeutic purposes. Specifically, we assess the use of vector-mediated RNAi for treatment of viral processes, solid cancers, lymphoproliferative disorders, and neurodegenerative and ocular diseases. In addition, we highlight further emerging applications, including stem cell therapies and animal transgenesis, as well as discuss some of the potential pitfalls and limitations inherent to the individual approaches. While we predict that eventual schemes will be shaped by our increasing understanding of the complexities of human RNAi biology, as well as by progressive refinements of viral shuttle designs, the potential scientific and medical benefits from a successful marriage of RNAi and gene therapy seem enormous.