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0031-6997/03/5504-629-648$7.00
Pharmacol Rev 55:629-648, 2003

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RNA Interference in Biology and Medicine

Ollivier Milhavet, Devin S. Gary and Mark P. Mattson

Laboratory of Neurosciences (O.M., M.P.M.), National Institute on Aging, Gerontology Research Center, Baltimore, Maryland; and Departments of Neurology (D.S.G.) and Neuroscience (M.P.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland

Abstract
I. Introduction
II. Principles of RNA Interference
    A. Post-Transcriptional Gene Silencing and the Discovery of RNA Interference
    B. Mechanism of RNA Interference
    C. Other Related Phenomena
III. Technical Considerations in the Use of RNA Interference
    A. Design and Synthesis of Small Interfering RNAs
    B. Construction of Plasmids and Viral Vectors for RNA Interference
    C. Transfection Methods
IV. Applications of RNA Interference to Establishing Gene Function
    A. Signal Transduction
    B. Cell Cycle Regulation
    C. Development
    D. Macromolecular Synthesis and Degradation
    E. Cell Motility
    F. Cell Death
    G. Viral Invasion/Replication
V. Therapeutic Applications of RNA Interference
    A. Cancer
    B. Infectious Diseases
    C. Cardiovascular and Cerebrovascular Diseases
    D. Neurodegenerative Disorders
VI. The Future of RNA Interference in Biology and Medicine
First discovered in plants the nematode Caenorhabditis elegans, the production of small interfering RNAs (siRNAs) that bind to and induce the degradation of specific endogenous mRNAs is now recognized as a mechanism that is widely employed by eukaryotic cells to inhibit protein production at a post-transcriptional level. The endogenous siRNAs are typically 19- to 23-base double-stranded RNA oligonucleotides, produced from much larger RNAs that upon binding to target mRNAs recruit RNases to a protein complexthat degrades the targeted mRNA. Methods for expressing siRNAs in cells in culture and in vivo using viral vectors, and for transfecting cells with synthetic siRNAs, have been developed and are being used to establish the functions of specific proteins in various cell types and organisms. RNA interference methods provide several major advantages over prior methods (antisense DNA or antibody-based techniques) for suppressing gene expression. Recent preclinical studies suggest that RNA interference technology holds promise for the treatment of various diseases. Pharmacologists have long dreamed of the ability to selectively antagonize or eliminate the function of individual proteins—RNAi technology may eventually make that dream a reality.

Address correspondence to: Mark P. Mattson, Laboratory of Neurosciences, National Institute on Aging, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224. E-mail: mattsonm{at}grc.nia.nih.gov




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