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Strategies for silencing human disease using RNA interference

Nature Reviews Genetics volume 8, pages 173–184 (2007)Cite this article

Key Points

  • Small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) serve as the effector molecules of RNA interference (RNAi). Important mechanistic advances have recently been made in understanding the diverse ways in which RNAi pathways regulate gene expression.

  • The potency and specificity of chemically synthesized siRNAs and expressed shRNAs are increased by designing these molecules so that they serve as substrates for the RNase III enzymes Drosha and Dicer. Expressed shRNAs can be designed to mimic the structures of endogenous microRNA (miRNA) transcripts.

  • Sequence-dependent off-target and immunostimulatory effects are concerns that must be addressed when designing siRNAs and shRNAs for therapeutic purposes. Saturation of RNAi pathway components should also be avoided by optimizing siRNA dosage and shRNA expression levels.

  • siRNAs are delivered systemically through lipid-based carriers and liganded nanoparticles. New methods have been developed that allow siRNAs to be targeted to specific cell-surface receptors.

  • Viral delivery vectors facilitate the stable expression of shRNAs in therapeutically relevant settings. Lentiviral, adenoviral and adeno-associated viral vectors are in development for RNAi gene-therapy strategies.

  • Clinical trials using RNAi-based therapies are currently under way for wet, age-related macular degeneration and respiratory syncytial virus infection. At present, RNAi-based therapies for other viral infections, cancer and neurodegenerative diseases are in preclinical development, and additional clinical trials will be initiated during 2007.

Abstract

Since the first description of RNA interference (RNAi) in animals less than a decade ago, there has been rapid progress towards its use as a therapeutic modality against human diseases. Advances in our understanding of the mechanisms of RNAi and studies of RNAi in vivo indicate that RNAi-based therapies might soon provide a powerful new arsenal against pathogens and diseases for which treatment options are currently limited. Recent findings have highlighted both promise and challenges in using RNAi for therapeutic applications. Design and delivery strategies for RNAi effector molecules must be carefully considered to address safety concerns and to ensure effective, successful treatment of human diseases.

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Figure 1: Mechanisms of RNA interference in mammalian cells.
Figure 2: RISC loading and activation.
Figure 3: RNA interference effector molecules.
Figure 4: Immunostimulatory effects of RNA interference.
Figure 5: Delivery of small interfering RNAs.
Figure 6: Viral delivery of short hairpin RNAs.

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Acknowledgements

We thank members of our laboratory for discussions and support. We apologize to any colleagues whose work could not be cited due to space limitations. This work was supported by grants from the US National Institutes of Health to J.J.R.

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  1. Division of Molecular Biology, Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, 1450 East Duarte Road, Duarte, 91010, California, USA

    Daniel H. Kim & John J. Rossi

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Correspondence to John J. Rossi.

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Competing interests

Daniel H. Kim & John J. Rossi. Strategies for silencing human disease using RNA interference. Nature Reviews Genetics 8, 173–184 (2007); doi:10.1038/nrg2006

John J. Rossi is a co-founder and equity holder in Calando Pharmaceuticals, Inc. (Pasadena, California, USA) — an RNAi company.

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Glossary

Short hairpin RNAs

(shRNAs). A class of small RNAs with a stem of 19–29 base pairs and a loop of 4–10 nucleotides that are processed by Dicer into small interfering RNAs. shRNAs are expressed from vectors to induce RNAi.

Interferons

A class of glycoproteins that are upregulated in response to exogenous ssRNA or dsRNA as a cellular defence mechanism against RNA viral infection.

Processing bodies

Cytoplasmic bodies that contain enzymes involved in mRNA turnover, such as the decapping enzymes DCP1 and DCP2, and sequester mRNAs from the translational machinery.

Polycistronic

A single RNA molecule that can generate several products. For miRNAs, a single polycistronic transcript contains multiple stem-loop structures encoding separate miRNAs.

Plasmacytoid dendritic cells

Cells of the immune system that recognize foreign pathogens through Toll-like receptors and other pattern-recognition receptors.

Endosome

A vesicle formed during the incorporation of extracellular material by endocytosis. Toll-like receptors are found in endosomal compartments.

Nanoparticle

Nanometre-scale particles that are formulated from polymers or phospholipids and are used as delivery vehicles for therapeutic applications.

Aptamer

RNA or DNA oligonucleotides selected from random pools of sequences that bind to specific receptors on the basis of their secondary structure.

Episome

A double-stranded, circular DNA molecule that replicates in the nucleus without integrating into the host genome.

Pseudotyping

Changing the ability of a viral vector to bind cell-surface receptors by altering its envelope proteins.

Hammerhead ribozyme

Small, self-cleaving catalytic RNAs with distinct secondary structures and highly conserved core residues that mediate cleavage.

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Kim, D., Rossi, J. Strategies for silencing human disease using RNA interference. Nat Rev Genet 8, 173–184 (2007). https://doi.org/10.1038/nrg2006

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