Interfering with disease: a progress report on siRNA-based therapeutics

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Abstract

RNA interference (RNAi) has rapidly advanced since its initial discovery to form the basis of a new class of therapeutics. De Fougerolles and colleagues discuss the challenges in the development of RNAi-based therapeutics, focusing on lead identification/optimization and effective delivery, and review the latest clinical results.

Abstract

RNA interference (RNAi) quietly crept into biological research in the 1990s when unexpected gene-silencing phenomena in plants and flatworms first perplexed scientists. Following the demonstration of RNAi in mammalian cells in 2001, it was quickly realized that this highly specific mechanism of sequence-specific gene silencing might be harnessed to develop a new class of drugs that interfere with disease-causing or disease-promoting genes. Here we discuss the considerations that go into developing RNAi-based therapeutics starting from in vitro lead design and identification, to in vivo pre-clinical drug delivery and testing. We conclude by reviewing the latest clinical experience with RNAi therapeutics.

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Most cited references 79

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Mechanisms of gene silencing by double-stranded RNA.

Gunter Meister, Thomas Tuschl (2004)

Double-stranded RNA (dsRNA) is an important regulator of gene expression in many eukaryotes. It triggers different types of gene silencing that are collectively referred to as RNA silencing or RNA interference. A key step in known silencing pathways is the processing of dsRNAs into short RNA duplexes of characteristic size and structure. These short dsRNAs guide RNA silencing by specific and distinct mechanisms. Many components of the RNA silencing machinery still need to be identified and characterized, but a more complete understanding of the process is imminent.

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Expression profiling reveals off-target gene regulation by RNAi.

Aimee Jackson, Steven Bartz, Janell M Schelter … (2003)

RNA interference is thought to require near-identity between the small interfering RNA (siRNA) and its cognate mRNA. Here, we used gene expression profiling to characterize the specificity of gene silencing by siRNAs in cultured human cells. Transcript profiles revealed siRNA-specific rather than target-specific signatures, including direct silencing of nontargeted genes containing as few as eleven contiguous nucleotides of identity to the siRNA. These results demonstrate that siRNAs may cross-react with targets of limited sequence similarity.

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Asymmetry in the assembly of the RNAi enzyme complex.

Dianne S. Schwarz, Gyorgy Hutvagner, Tingting Du … (2003)

A key step in RNA interference (RNAi) is assembly of the RISC, the protein-siRNA complex that mediates target RNA cleavage. Here, we show that the two strands of an siRNA duplex are not equally eligible for assembly into RISC. Rather, both the absolute and relative stabilities of the base pairs at the 5' ends of the two siRNA strands determine the degree to which each strand participates in the RNAi pathway. siRNA duplexes can be functionally asymmetric, with only one of the two strands able to trigger RNAi. Asymmetry is the hallmark of a related class of small, single-stranded, noncoding RNAs, microRNAs (miRNAs). We suggest that single-stranded miRNAs are initially generated as siRNA-like duplexes whose structures predestine one strand to enter the RISC and the other strand to be destroyed. Thus, the common step of RISC assembly is an unexpected source of asymmetry for both siRNA function and miRNA biogenesis.

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Contributors

Antonin de Fougerolles: tdefougerolles@alnylam.com

Bio :

Antonin de Fougerolles is a senior director of research at Alnylam Pharmaceuticals, a biopharmaceutical company at the forefront of developing novel therapeutics based on RNA interference (RNAi). He completed his Ph.D. in immunology at Harvard University, Cambridge, Massachusetts, USA, and following postdoctoral studies, he joined Biogen Idec where he led several drug-discovery programmes focussing on the treatment of autoimmune, inflammatory and fibrotic diseases. He joined Alnylam Pharmaceuticals in 2003 and has published on various aspects of RNAi therapeutics, including the first report on the presence of TLR7-dependent immunostimulatory motifs. His areas of research include: development of RNAi therapeutics for the treatment of human disorders, including infectious and inflammatory diseases, and investigation into RNAi delivery technologies.

Hans-Peter Vornlocher:

Bio :

Hans-Peter Vornlocher is a managing director of research at Alnylam Europe AG. He received a Ph.D. in biochemistry from the University of Bayreuth, Germany, in 1995, and spent 3 years doing postdoctoral research at the University of California Davis, USA, studying mechanisms of protein synthesis. He also worked as a researcher at the Institute for Molecular Biology and Tumour Research in Marburg and the Max-Planck-Institute for Biophysical Chemistry in Göttingen, Germany, where his work focused on the characterization of the structural dynamics of the spliceosome. Hans-Peter Vornlocher joined Alnylam Europe AG (then Ribopharma AG) in 2001 and since then has focused on the development of RNAi-based therapeutics. He has published a series of papers on different aspects of RNAi therapeutics, including the first report on therapeutic silencing in the liver mediated by systemically administered siRNAs.

John Maraganore:

Bio :

John Maraganore is President and Chief Executive Officer of Alnylam Pharmaceuticals. Prior to joining Alnylam in 2002, he served as an officer and a member of the management team for Millennium Pharmaceuticals, Inc. As senior vice president of Strategic Product Development for Millennium he was responsible for the company's product franchises in oncology and cardiovascular, inflammation and metabolic diseases. Before Millennium he served as Director of Molecular Biology and Director of Market and Business Development at Biogen Idec. At Biogen, John Maraganore led the discovery and development of Angiomax (bivalirudin for injection, formerly HirulogTM) currently marketed by The Medicines Company. Prior to Biogen, he was a scientist at ZymoGenetics, Inc. and the Upjohn Company. He received his M.Sc. and Ph.D. in biochemistry and molecular biology from the University of Chicago, Illinois, USA.

Judy Lieberman: Lieberman@cbr.med.harvard.edu

Bio :

Judy Lieberman is a senior investigator at the CBR Institute and Professor of Paediatrics at Harvard Medical School, Massachusetts, USA. She directs the Division of AIDS at Harvard Medical School. She received a Ph.D. in physics from Rockefeller University and an M.D. from Harvard and Massachusetts Institute of Technology. She is a board-certified haematologist. She has been at the forefront in harnessing RNA interference for disease prevention and therapy, especially for viral diseases and cancer. She was the first to show that RNAi could be used to protect mice from disease. Her laboratory also studies how cytotoxic T lymphocytes kill viral infected or cancerous target cells, and how T-cell effector immune responses are regulated in the setting of chronic infection.

Journal

Journal ID (nlm-ta): Nat Rev Drug Discov

Journal ID (iso-abbrev): Nat Rev Drug Discov

Title: Nature Reviews. Drug Discovery

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1474-1776

ISSN (Electronic): 1474-1784

Publication date (Print): 2007

Volume: 6

Issue: 6

Pages: 443-453

Affiliations

[1 ]Antonin de Fougerolles and John Maraganore are at Alnylam Pharmaceuticals Inc., 300 Third Street, Cambridge, Massachusetts 02142, USA., ,

[2 ]Hans-Peter Vornlocher is at Alnylam Europe AG, Fritz-Hornschuch-Str. 9, Kulmbach 95326, Germany., ,

[3 ]Judy Lieberman is at the CBR Institute for Biomedical Research, 200 Longwood Avenue, Boston, Massachusetts 02115, USA., ,

Article

Publisher ID: BFnrd2310

DOI: 10.1038/nrd2310

PMC ID: 7098199

PubMed ID: 17541417

SO-VID: 0087564c-8535-4bb3-bccc-d57e8dc51e4e

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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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Interfering with disease: a progress report on siRNA-based therapeutics

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Aging Pathobiology and Therapeutics

Most cited references 79

Mechanisms of gene silencing by double-stranded RNA.

Expression profiling reveals off-target gene regulation by RNAi.

Asymmetry in the assembly of the RNAi enzyme complex.

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Cited by 229

Most referenced authors 3,214