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Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis

  1. Hongliu Ding1,†,
  2. Dianne S. Schwarz1,†,
  3. Alex Keene1,
  4. El Bachir Affar4,
  5. Laura Fenton1,
  6. Xugang Xia1,
  7. Yang Shi4,
  8. Phillip D. Zamore1,*,
  9. Zuoshang Xu1,2,3,*

Article first published online: 23 JUL 2003

DOI: 10.1046/j.1474-9728.2003.00054.x

Issue

Aging Cell

Aging Cell

Volume 2, Issue 4, pages 209–217, August 2003

Additional Information

How to Cite

Ding, H., Schwarz, D. S., Keene, A., Affar, E. B., Fenton, L., Xia, X., Shi, Y., Zamore, P. D. and Xu, Z. (2003), Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis. Aging Cell, 2: 209–217. doi: 10.1046/j.1474-9728.2003.00054.x

Author Information

  1. 1

    Departments of Biochemistry and Molecular Pharmacology,

  2. 2

    Cell Biology, and

  3. 3

    Neuroscience Program, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01605–2324, USA

  4. 4

    Department of Pathology, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115, USA

  1. †

    These authors contributed equally to the paper.

*Zuoshang Xu, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01605–2324, USA. Tel.: +1 508 856 3309; fax: +1 508 856 8390; e-mail: zuoshang.xu@umassmed.edu Phillip Zamore, as above. Tel.: +1 508 856 2191; fax: +1 508 856 2003; e-mail: phillip.zamore@umassmed.edu

  • †

    These authors contributed equally to the paper.

Publication History

  1. Issue published online: 23 JUL 2003
  2. Article first published online: 23 JUL 2003
  3. Accepted for publication 22 May 2003

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Keywords:

  • ALS;
  • motor neuron disease;
  • neurodegenerative disease;
  • RNA interference;
  • shRNA;
  • siRNA

Summary

RNA interference (RNAi) can achieve sequence-selective inactivation of gene expression in a wide variety of eukaryotes by introducing double-stranded RNA corresponding to the target gene. Here we explore the potential of RNAi as a therapy for amyotrophic lateral sclerosis (ALS) caused by mutations in the Cu, Zn superoxide dismutase (SOD1) gene. Although the mutant SOD1 is toxic, the wild-type SOD1 performs important functions. Therefore, the ideal therapeutic strategy should be to selectively inhibit the mutant, but not the wild-type SOD1 expression. Because most SOD1 mutations are single nucleotide changes, to selectively silence the mutant requires single-nucleotide specificity. By coupling rational design of small interfering RNAs (siRNAs) with their validation in RNAi reactions in vitro and in vivo, we have identified siRNA sequences with this specificity. A similarly designed sequence, when expressed as small hairpin RNA (shRNA) under the control of an RNA polymerase III (pol III) promoter, retains the single-nucleotide specificity. Thus, RNAi is a promising therapy for ALS and other disorders caused by dominant, gain-of-function gene mutations.

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