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1.
Silencing of gene expression by RNA interference (RNAi) has become a powerful tool for functional genomics in mammalian cells. Furthermore, RNAi holds promise as a simple, fast and cost-effective approach to studying mammalian gene function in vivo and as a novel therapeutic approach. This review provides an overview of the progress of RNAi in vivo, with emphasis on systemic/local siRNA delivery, viral shRNA vectors, shRNA vector transgenic mice and conditional systems to control shRNA vectors. Taken together, the data from 80 in vivo studies show that RNAi is a useful tool that offers new opportunities for functional genomics in mice. 相似文献
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RNAi-based drug discovery and its application to therapeutics 总被引:2,自引:0,他引:2
Hokaiwado N Takeshita F Banas A Ochiya T 《IDrugs : the investigational drugs journal》2008,11(4):274-278
The discovery of RNA interference (RNAi) for target-specific gene silencing via short interfering RNA (siRNA) has rapidly created a powerful tool for the exploration of pathogenesis of disease. The identification of this remarkable molecular pathway has manifested in the new field of RNAi therapy. In efforts to establish the therapeutic application of RNAi therapy, a major focus has been on target gene-specific siRNA-delivery technology in vivo. In particular, creating a pinpoint delivery system for siRNAs is a priority because such a system would be a key technology for the development of the next generation of drugs, including anticancer therapies. Drug discovery studies and novel treatments based on RNAi are currently targeting a wide range of diseases, including viral infections and cancer. This feature review focuses on recent progress in the nonviral systemic delivery of siRNA in animal models and in clinical trials, as well as on the application of microRNAs in RNAi therapy. 相似文献
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Carstea ED Hough S Wiederholt K Welch PJ 《IDrugs : the investigational drugs journal》2005,8(8):642-647
In recent years, the recognition of non-protein coding RNAs as a functional effector of genetic expression has been highlighted by the discovery of RNA interference (RNAi). RNAi is an intracellular phenomenon that enables the eukaryotic cell to utilize double-stranded RNA molecules to silence gene expression in a sequence-specific manner. The short interfering RNA (siRNA) pathway has been intensively investigated and continues to serve as the basis for the development of potent molecular genetic tools. The power of this technology is most clearly evidenced by the fact that siRNA effector molecules can be chemically synthesized and exogenously delivered to specifically target and silence any gene of choice. This capability enables not only basic research, but also opens the door to a new therapeutic modality. Furthermore, the introduction of certain chemical modifications to siRNA effectors can produce a more robust knockdown of gene expression, hence, optimizing serum stability and increasing target specificity yet limiting the induction of cellular stress response, which are key features for in vivo delivery and successful therapeutics. This article outlines the progress in the development of differentially modified siRNA duplexes and their potential role as human therapeutics. 相似文献
4.
Chemical modification of gene silencing oligonucleotides for drug discovery and development 总被引:4,自引:0,他引:4
Gene silencing, the specific inhibition of unwanted gene expression by blocking mRNA activity, has long appeared to be an ideal strategy to leverage new genomic knowledge for drug discovery and development. But effective delivery has continuously been a limiting factor. In the past two decades, valuable progress has been made through the development of various chemically modified single-stranded antisense oligonucleotides, with improved properties such as enhanced stability, higher affinity and lower toxicity. Although short interfering RNA (siRNA) can provide better specificity and stronger efficacy by means of RNA interference (RNAi), in vivo delivery of siRNA often relies on plasmids or vectors, both of which present therapeutic safety risks. This review presents a brief history of gene silencing from PS-ODN through siRNA, introduces DNP-RNA--a more potent and easily delivered gene silencing platform--and compares its performance with that of siRNA and other AS-oligonucleotides. 相似文献
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RNA interference (RNAi) is a gene silencing process mediated by double-stranded RNA (dsRNA). The silencing process is comprised of an initiation step, in which small interfering RNA (siRNA) is introduced to the cell, and an effector step, which involves degrading mRNA molecules of the target gene. RNA interference has been observed in most organisms from plants to vertebrates. As a gene silencing approach, RNAi has proven to be extremely useful in characterizing gene function and developing new tools in cancer therapy and drug delivery. The development of RNAi-related technologies is an emerging area in biomedical research. In this review, recent progress in the application of RNAi to the study of transport proteins is summarized and evaluated; the advantages, disadvantages and future directions of RNAi technology are discussed. 相似文献
7.
RNA interference (RNAi), as an evolutionarily conserved mechanism for silencing gene expression, is realized through the actions of both small interference RNA (siRNA) and microRNA. Since its discovery, siRNA has been rapidly deployed not only for the elucidation of gene function, but also for identification of drug targets and as a powerful therapeutic approach for a variety of diseases. In this review, we briefly introduce the mechanisms of RNAi, methods of siRNA design and delivery, and summarized recent researches on the therapeutic potential of RNAi for immune diseases. 相似文献
8.
RNA干扰(RNAi)是由双链RNA介导,在转录后mRNA水平关闭相应基因表达的新基因阻断技术,在基因功能研究、基因治疗方面已显示出巨大的前景。同时,RNAi的分子机制研究也不断取得进展,包括对基因转录后水平、翻译水平、基因甲基化及沉默信号的传递等层次的研究。清晰阐述RNAi作用机理将为大规模的基因系统筛查、新基因的发现、人类肿瘤及难治性疾病的基因治疗提供重要理论依据和有力工具。 相似文献
9.
RNA interference as a tool for Alzheimer's disease therapy 总被引:1,自引:0,他引:1
Orlacchio A Bernardi G Orlacchio A Martino S 《Mini reviews in medicinal chemistry》2007,7(11):1166-1176
RNA interference is a biological process that controls gene silencing in all living cells. Targeting the RNA interference system represents a novel therapeutic strategy able to intercede with multiple disease-related genes and to target many neurodegenerative diseases. Recently, the design of small interfering RNA-selective compounds has become more straightforward because of the significant progress made in predictive modeling for new therapeutic approaches. Although in vivo delivery of RNA interference remains a significant obstacle, new data show that RNAi blocks gene function in vivo, suggesting a potential therapeutic approach for humans. Some groups have demonstrated the efficacy of RNAi therapy in Alzheimer's disease. Results, based on animal models, show a down-regulation of the amyloid precursor protein and a consequent reduction of the amyloid-beta peptide accumulation in the brain or the inactivation of beta-secretase (BACE1). Indeed, lentiviral vectors expressing siRNAs targeting BACE1 reduce amyloid production and the neurodegenerative and behavioural deficit in APP transgenic mice. This review highlights recent advances in RNA research and focuses on strengths and weaknesses of RNAi compounds in Alzheimer's disease. 相似文献
10.
《Drug metabolism reviews》2012,44(4):705-723
RNA interference (RNAi) is a gene silencing process mediated by double-stranded RNA (dsRNA). The silencing process is comprised of an initiation step, in which small interfering RNA (siRNA) is introduced to the cell, and an effector step, which involves degrading mRNA molecules of the target gene. RNA interference has been observed in most organisms from plants to vertebrates. As a gene silencing approach, RNAi has proven to be extremely useful in characterizing gene function and developing new tools in cancer therapy and drug delivery. The development of RNAi-related technologies is an emerging area in biomedical research. In this review, recent progress in the application of RNAi to the study of transport proteins is summarized and evaluated; the advantages, disadvantages and future directions of RNAi technology are discussed. 相似文献
11.
Chakraborty C 《Current drug targets》2007,8(3):469-482
In recent years, RNA interference (RNAi) is one of the most important discoveries. RNAi is an evolutionarily conserved mechanism for silencing gene expression by targeted degradation of mRNA. Short double-stranded RNAs, known as small interfering RNAs (siRNA), are incorporated into an RNA-induced silencing complex that directs degradation of RNA containing a homologous sequence. siRNA has been shown to work in mammalian cells, and can inhibit viral infection and control tumor cell growth in vitro. Recently, it has been shown that intravenous injection of siRNA or of plasmids expressing sequences processed to siRNA can protect mice from autoimmune and viral hepatitis. In this review, we have discussed about the discovery of RNAi and siRNA, mechanism of siRNA mediated gene silencing, mediated gene silencing in mammalian cells, vectored delivery of siRNA, pharmaceutical potentiality of siRNA from mice to human. We have also discussed about promise and hurdles of siRNA or RNAi that could provide an exciting new therapeutic modality for treating infection, cancer, neurodegenerative disease, antiviral diseases (like viral hepatitis and HIV-1), huntington's disease, hematological disease, pain research and therapy, sarcoma research and therapy and many other illness in details. It will be a tool for stem cell biology research and now, it is a therapeutic target for gene-silencing. 相似文献
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Yuki Takahashi 《Advanced drug delivery reviews》2009,61(9):760-766
RNA interference (RNAi) is a potent and specific gene silencing event in which small interfering RNA (siRNA) degrades target mRNA. Therefore, RNAi is of potential use as a therapeutic approach for the treatment of a variety of diseases in which aberrant expression of mRNA causes a problem. RNAi can be achieved by delivering siRNA or vectors that transcribe siRNA or short-hairpin RNA (shRNA). The aim of this review is to examine the potential of nonviral vector-mediated RNAi technology in treating diseases. The characteristics of plasmid DNA expressing shRNA were compared with those of siRNA, focusing on the duration of gene silencing, delivery to target cells and target specificity. Recent progresses in prolonging the RNAi effect, improving the delivery to target cells and increasing the specificity of RNAi in vivo are also reviewed. 相似文献
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Anubrata Ghosal Ahmad Humayan Kabir Abul Mandal 《Central European Journal of Medicine》2011,6(2):137-147
RNA interference is a technique that has become popular in the past few years. This is a biological method to detect the activity
of a specific gene within a cell. RNAi is the introduction of homologous double stranded RNA to specifically target a gene’s
product resulting in null or hypomorphic phenotypes. This technique involves the degradation of specific mRNA by using small
interfering RNA. Both microRNA (miRNA) and small interfering RNA (siRNA) are directly related to RNA interference. RNAi mechanism
is being explored as a new technique for suppressing gene expression. It is an important issue in the treatment of various
diseases. This review considers different aspects of RNAi technique including its history of discovery, molecular mechanism,
gene expression study, advantages of this technique against previously used techniques, barrier associated with this technique,
and its therapeutic application. 相似文献
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Hoyer D 《Current opinion in drug discovery & development》2007,10(2):122-129
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Hassan A 《Recent patents on cardiovascular drug discovery》2006,1(2):141-149
RNA interference (RNAi) in eukaryotes is a recently identified phenomenon in which small double stranded RNA molecules called short interfering RNA (siRNA) interact with messenger RNA (mRNA) containing homologous sequences in a sequence-specific manner. Ultimately, this interaction results in degradation of the target mRNA. Because of the high sequence specificity of the RNAi process, and the apparently ubiquitous expression of the endogenous protein components necessary for RNAi, there appears to be little limitation to the genes that can be targeted for silencing by RNAi. Thus, RNAi has enormous potential, both as a research tool and as a mode of therapy. Several recent patents have described advances in RNAi technology that are likely to lead to new treatments for cardiovascular disease. These patents have described methods for increased delivery of siRNA to cardiovascular target tissues, chemical modifications of siRNA that improve their pharmacokinetic characteristics, and expression vectors capable of expressing RNAi effectors in situ. Though RNAi has only recently been demonstrated to occur in mammalian tissues, work has advanced rapidly in the development of RNAi-based therapeutics. Recently, therapeutic silencing of apoliporotein B, the ligand for the low density lipoprotein receptor, has been demonstrated in adult mice by systemic administration of chemically modified siRNA. This demonstrates the potential for RNAi-based therapeutics, and suggests that the future for RNAi in the treatment of cardiovascular disease is bright. 相似文献
18.
Gene silencing mediated by small interfering RNAs in mammalian cells 总被引:52,自引:0,他引:52
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RNA interference for mammalian cells 总被引:5,自引:0,他引:5
Oshiumi H Begum NA Matsumoto M Seya T 《Nihon yakurigaku zasshi. Folia pharmacologica Japonica》2002,120(2):91-95
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The discovery of RNA interference (RNAi) in eukaryotic cells has been the major recent breakthrough in molecular and cell biology. RNAi machineries exert biological functions in gene regulation, genome defense and chromatin architecture and dynamics. The potential of RNAi to silence any gene of interest in a highly specific and efficient manner via double-stranded RNA (dsRNA) has literally revolutionized modern genetics. RNAi-based functional genomics now permits, for the first time, to evaluate the cellular role of individual gene products on a genome-wide scale in higher organisms like mammals, presenting an alternative to the generation of animal knockouts often doomed to failure because of a lethal phenotype. RNAi has had an enormous impact on the development of novel disease models in animals, and it is likely that small interfering RNAs (siRNAs), which are the trigger molecules for RNA silencing, will become an invaluable tool for the treatment of genetic diseases. First clinical trials, using siRNAs directed against the vascular endothelial growth factor (VEGF) or one of its receptors, have been initiated recently for the treatment of age-related macular degeneration. Improving guidelines for the rational design of siRNAs, based on recent progress in understanding the mechanisms underlying RNAi, as well as the introduction of chemical modifications into siRNAs are expected to improve their pharmacokinetic and pharmacodynamic properties for in vivo applications. Finally, successful therapeutic application of RNAi will depend on the development of improved siRNA delivery strategies that combine high specificity and efficiency with a low immunostimulatory and tumorigenic potential. 相似文献