The huge world of small RNAs: regulating networks of microRNAs (review).

MicroRNAs (miRNAs) are a recently discovered class of small, non-coding RNAs which do not code proteins. MiRNAs regulate gene expression by inhibiting protein translation from the messenger RNA. MiRNAs may function in networks, forming a complex relationship with diseases. Furthermore, specific miRNAs have significant correlation with diseases of divergent origin. After identification of disease-associated miRNAs, their tissue expression could be altered in a beneficial way by inhibiting or mimicking their effects. Thus, modifying the expression of miRNAs is a potential future gene-therapeutic tool to influence post-transcriptional regulation of multiple genes in a single therapy. In this review we introduce the biogenesis, mechanism of action and future aspects of miRNAs. Research on the post-transcriptional regulation of gene expression by miRNA may reshape our understanding of diseases and consequently may bring new diagnostic markers and therapeutic agents. Therapeutic use of miRNAs is already under clinical investigation in RNA interference trials.

Can siRNA technology provide the tools for gene therapy of the future?

A new era in genetics has started 15 years ago, when co-suppression in petunia has been discovered. Later, co-suppression was identified as RNA interference (RNAi) in many plant and lower eukaryote animals. Although an ancient antiviral host defense mechanism in plants, the physiologic role of RNAi in mammals is still not completely understood. RNAi is directed by short interfering RNAs (siRNAs), one subtype of short double stranded RNAs. In this review we summarize the history and mechanisms of RNAi. We also aim to highlight the correlation between structure and efficacy of siRNAs. Delivery is the most important obstacle for siRNA based gene therapy. Viral and nonviral deliveries are discussed. In vivo delivery is the next obstacle to clinical trials with siRNAs. Although hydrodynamic treatment is effective in animals, it cannot be used in human therapy. One possibility is organ selective catheterization. The known side effects of synthesized siRNAs are also discussed. Although there are many problems to face in this new field of gene therapy, successful in vitro and in vivo experiments raise hope for treating human disease with siRNA.