For Personal Use. Only Reproduce with Permission the Lancet Publishing Group. Molecular Medicine for the Brain: Silencing of Disease Genes with Rna Interference
For Personal Use. Only Reproduce with Permission the Lancet Publishing Group. Molecular Medicine for the Brain: Silencing of Disease Genes with Rna Interference
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B. Davidson;H. Paulson
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作者：
B. Davidson;H. Paulson
最近发现的RNA干扰（RNAi）已经彻底改变了生物学研究，现在有望成为人类疾病的潜在治疗方法。目前无法治愈的神经系统疾病是特别有吸引力的目标。科学家们已经成功地利用RNAi在体外抑制显性疾病基因；在某些情况下，这种抑制是等位基因特异性的，使致病等位基因沉默，同时维持正常等位基因的表达。现在的挑战是将这种强大的技术引入动物体内模型，以抑制疾病基因并纠正疾病表型。面对这一挑战，研究应该受益于病毒和非病毒向大脑输送治疗的最新进展。RNA干扰（RNA interference, RNAi）是一种简单而意义深远的生物学过程。通过使用这项最新开发的技术——基于存在于多种生物中的自然发生的分子机制，如植物、秀丽隐杆线虫、果蝇和哺乳动物——我们可以抑制疾病基因的表达或阻断破坏性途径。世界各地的研究人员已经将RNAi用于基础研究，现在正在开发用于治疗目的的诱导RNAi的工具。在这篇综述中，我们将简要介绍RNAi是如何完成的，重点是RNAi在神经系统疾病的潜在治疗应用。在过去几年中，RNAi的相对容易和特异性使其成为研究的热点。然而，重要的是要认识到RNAi可以通过几种不同的机制来完成，使用不同类型的RNA；自然产生的、化学合成的和通过重组方法设计的。Scherer和Rossi最近对沉默技术和RNAi进行了详细的比较。分子生物学的中心法则是信息从DNA到RNA再到蛋白质的定向流动。最近的研究证明，RNA可以双向调节这种信息流。在RNAi中，与特定靶基因互补的小双链RNA通过抑制翻译或降解靶信使RNA （mRNA）来抑制蛋白质表达。自然产生的抑制性RNA可以控制大脑和其他地方的特定靶基因表达。科学家们现在可以利用这一生物过程，创造出小的抑制RNA分子来抑制几乎任何基因的表达。在疾病治疗的重要临床前研究中，抑制性RNA主要通过两种方法引入细胞（图1）。第一种是短寡核苷酸的双链，通常彼此完全互补，…
145 Reviews The recent discovery of RNA interference (RNAi) has revolutionised biological research and now holds promise as a potential therapy for human diseases. Currently untreatable neurological diseases are especially attractive targets. Scientists have already succeeded in using RNAi to suppress dominant disease genes in vitro; in some cases, this suppression has been allele-specific, silencing the disease-causing allele while maintaining expression of the normal allele. The challenge now is to bring this powerful technology in vivo to animal models to suppress disease genes and correct disease phenotypes. In the confrontation of this challenge, research should benefit from recent advances in viral and non-viral delivery of therapy to the brain. RNA interference (RNAi) is a simple biological process with profound implications. By use of this recently developed technology—which is based on naturally occurring molecular machinery present in organisms as diverse as plants, Caenorhabditis elegans, Drosophilia, and mammals— we can inhibit expression of a disease gene or block a destructive pathway. 1 Researchers worldwide have used RNAi for basic research, and are now developing tools to induce RNAi for therapeutic purposes. In this review, we will briefly describe how RNAi is accomplished, with a focus on potential therapeutic applications of RNAi for neurological disease. The relative ease and specificity with which RNAi can be accomplished has made it the subject of intense study over the past few years. However, it is important to recognise that RNAi can be accomplished by several different mechanisms, using distinct types of RNA; naturally occuring, chemically synthesised and those engineered through recombinant methods. Scherer and Rossi 2 recently made a detailed comparison of silencing techniques and RNAi. Mechanism The central dogma in molecular biology has been the directional flow of information from DNA to RNA to protein. Recent work now proves that RNA can bidirectionally regulate this flow of information. In RNAi, small duplexes of RNA complementary to specific target genes suppress protein expression by inhibiting translation or degrading the targeted messenger RNA (mRNA). Naturally occurring inhibitory RNA can impart control over specific target-gene expression in the brain and elsewhere. Scientists can now take advantage of this biological process and create small inhibitory RNA molecules to suppress the expression of almost any gene. In important preclinical studies for disease therapies, inhibitory RNA has been introduced into cells by two main methods (figure 1). In the first, a duplex of short oligonucleotides, generally perfectly complementary to each other, …