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Technology Insight: therapeutic RNA interference—how far from the neurology clinic?

Nature Clinical Practice Neurology volume 3, pages 394–404 (2007)Cite this article

Abstract

As an evolutionarily conserved cellular pathway to regulate endogenous gene expression, RNA interference (RNAi) has been implicated in diverse biological processes. Biologists now routinely exploit this cellular pathway to suppress virtually any target gene in a sequence-specific manner, including dominantly acting genes that cause incurable neurodegenerative disorders. The development of RNAi as potential therapy for such diseases has generated considerable interest, partly because of the success of early studies of therapeutic RNAi in rodent models for a range of neurodegenerative diseases. In this article, we review the progress of RNAi therapy to date, and assess the challenges ahead for the application of such therapy to neurodegenerative diseases. We discuss the various strategies that might be used to achieve this goal, outline the preclinical studies that have already been completed, and highlight the experimental questions that need to be answered before human clinical trials can begin.

Key Points

  • RNA interference (RNAi) is a naturally occurring biological pathway in which small, double-stranded RNA molecules suppress gene expression in an exquisitely sequence-specific manner

  • Exogenous manipulation of RNAi is being explored as a powerful method of silencing disease-causing genes in incurable neurological disorders

  • Preclinical trials in animal models of various neurodegenerative diseases have demonstrated the feasibility and efficacy of this approach

  • Research efforts are invested in developing viral and nonviral methods of delivering RNAi-mediating molecules to various target brain regions

  • The safety of manipulating the RNAi pathway in the brain, where it participates in synaptic function, neuronal differentiation and brain development, needs to be carefully addressed

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Figure 1: The process of RNA interference and its manipulation

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Acknowledgements

Work on RNA interference in the authors' laboratories has been funded by grants from American Federation for Aging Research (HLP), Dystonia Medical Research Foundation (PG) and NIH (PO1 NS050210, directed by Beverly Davidson, University of Iowa).

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Authors and Affiliations

  1. P Gonzalez-Alegre is an Assistant Professor of Neurology at the University of Iowa, Iowa City, IA, USA.,

    Pedro Gonzalez-Alegre

  2. HL Paulson is the Lucile Groff Professor of Neurology at the University of Michigan, Ann Arbor, MI, USA.,

    Henry L Paulson

Authors
  1. Pedro Gonzalez-Alegre
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  2. Henry L Paulson
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Corresponding author

Correspondence to Henry L Paulson.

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Competing interests

HL Paulson has received honoraria from Athena Diagnostics and has acted as a consultant for Sirna Therapeutics. P Gonzalez-Alegre declared he has no competing interests.

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Gonzalez-Alegre, P., Paulson, H. Technology Insight: therapeutic RNA interference—how far from the neurology clinic?. Nat Rev Neurol 3, 394–404 (2007). https://doi.org/10.1038/ncpneuro0551

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