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Amyotrophic lateral sclerosis and gene therapy

Nature Clinical Practice Neurology volume 2, pages 462–463 (2006)Cite this article

With the identification of the genes and proteins involved in the etiology of neurodegenerative diseases, and the development of new viral tools for gene delivery, modulating the function of disease-associated genes as a therapy has become an increasingly realistic possibility. This approach is particularly applicable to amyotrophic lateral sclerosis (ALS), the dominant clinical manifestation of which is weakness that progresses to paralysis, with ensuing respiratory failure and death within 3–5 years of onset. A significant proportion of familial ALS cases are caused by a dominant mutation in the gene encoding superoxide dismutase (SOD1) that confers an aberrant toxic property on the protein; in principle, these cases could be amenable to treatment employing a gene-silencing strategy.

RNA interference (RNAi)—a post-transcriptional gene-silencing approach in which small double-stranded RNA molecules (small interfering RNAs or siRNAs) mediate the destruction of messenger RNAs (mRNAs) in a sequence-specific fashion—is one way to downregulate protein expression. Double-stranded RNAs formed by specific binding through standard base-pairing of an siRNA molecule to a target mRNA are recognized by the Dicer complex, a cytosolic set of enzymes that degrade the mRNA (but not the siRNA), thereby preventing further translation of protein.1 RNAi works brilliantly in cultured cells, in which nearly unlimited amounts of siRNA-encoding DNA can be introduced. Approximately 50% knockdown of target mRNA has been achieved with stabilized siRNA infused into the cerebral spinal fluid, although distribution within the CNS was limited.2 Despite attempts to stabilize siRNAs synthesized in vitro so as to enhance their biological half-lives after direct delivery to cells in animals,3 these molecules are short-lived—a serious issue for their use as a therapy.

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Authors and Affiliations

  1. Department of Neurosciences,

    Timothy M Miller & Don W Cleveland

  2. Laboratory for Cell Biology, Ludwig Institute for Cancer Research,

    Timothy M Miller & Don W Cleveland

  3. the University of California, San Diego, La Jolla, CA, USA

    Timothy M Miller & Don W Cleveland

  4. Director of the Center for Neurologic Study and a Skaggs Clinical Scholar at Scripps Research Institute, La Jolla, CA, USA

    Richard A Smith

Authors
  1. Timothy M Miller
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  2. Richard A Smith
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  3. Don W Cleveland
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Correspondence to Don W Cleveland.

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Competing interests

DW Cleveland and RA Smith have a consulting agreement with Isis Pharmaceutical Corporation. Along with ongoing compensation, they and their institutional employers could materially benefit if a therapeutic for amyotrophic lateral sclerosis results from their work. TM Miller declared he has no competing interests.

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Miller, T., Smith, R. & Cleveland, D. Amyotrophic lateral sclerosis and gene therapy. Nat Rev Neurol 2, 462–463 (2006). https://doi.org/10.1038/ncpneuro0270

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