RNA Interference Mechanisms, Technical Challenges, and Therapeutic Opportunities

Chapter 1

NA Interference: Mechanisms, Technical Challenges, R

and Therapeutic Opportunities



The ability to inhibit gene expression via RNA interference (RNAi) has a broad therapeutic potential for

various human diseases such as infections and cancers. Recent advances in mechanistic understanding of RNAi have improved the design of functional small interfering (si) RNAs with superior potency and speci city. With respect to delivery, new developments in delivery strategies have facilitated preclinical and clinical siRNA applications. This review provides valuable insights to guide the design and delivery of therapeutic siRNAs.

Key words RNAi , siRNA , Delivery materials , Clinical trials , Functional siRNAs 1Introduction

lthough a comparable mechanism had been described in plants A

earlier, Fire and Mello showed that double-stranded (ds) RNA can effectively silence gene expression, when introduced into

1 ]. It was later discovered that dsRNA was Caenorhabditis elegans [

processed into 21–25 nucleotide fragments when introduced into

2 , 3 ]. These fragments were termed small inter-Drosophila cells [

fering (si) RNAs and proved to be the main effectors of RNA inter-

4 ]. Analysis of the ference (RNAi) induction in mammalian cells [

silencing phenomena in various species revealed that RNAi is a widespread natural phenomenon that is conserved across fungi, plants, and animals, and is induced not only by exogenous siRNAs, but also several endogenous small RNA species such as microRNAs

5 ]. RNAi is involved in sev-(miRNAs) and piwi-interacting RNAs [

eral processes such as cell growth, tissue differentiation, hetero-chromatin formation, and cell proliferation. Accordingly, RNAi dysfunction is linked to cardiovascular diseases, neurological disor-

6 ]. Although the use of synthetic siRNAs shows ders, and cancers [

great therapeutic promise, challenges with delivery as well harmful off-target effects need to be resolved.

Mouldy Sioud (ed.), RNA Interference: Challenges and Therapeutic Opportunities, Methods in Molecular Biology, vol. 1218, DOI 10.1007/978-1-4939-1538-5_1, © Springer Science+Business Media New York 2015


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