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Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model

Nature Medicine volume 11, pages 429–433 (2005)Cite this article

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the selective death of motor neurons in the brain and spinal cord1. Some familial cases of ALS are caused by dominant mutations in the gene encoding superoxide dismutase (SOD1)2,3,4. The emergence of interfering RNA (RNAi) for specific gene silencing could be therapeutically beneficial for the treatment of such dominantly inherited diseases5,6,7. We generated a lentiviral vector to mediate expression of RNAi molecules specifically targeting the human SOD1 gene (SOD1). Injection of this vector into various muscle groups of mice engineered to overexpress a mutated form of human SOD1 (SOD1G93A) resulted in an efficient and specific reduction of SOD1 expression and improved survival of vulnerable motor neurons in the brainstem and spinal cord. Furthermore, SOD1 silencing mediated an improved motor performance in these animals, resulting in a considerable delay in the onset of ALS symptoms by more than 100% and an extension in survival by nearly 80% of their normal life span. These data are the first to show a substantial extension of survival in an animal model of a fatal, dominantly inherited neurodegenerative condition using RNAi and provide the highest therapeutic efficacy observed in this field to date.

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Figure 1: Silencing of SOD1 expression in vitro using EIAV-mediated expression of shRNAs.
Figure 2: Silencing of mutant SOD1 expression in vivo delays onset of ALS and extends survival of SOD1G93A mice.
Figure 3: Silencing of SOD1 expression using shRNA mediates improved motor performance in SOD1G93A transgenic mice.
Figure 4: Motor neuron survival is improved by RNAi-mediated silencing of SOD1.

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Acknowledgements

Many thanks to the Virology and Neurobiology teams at Oxford BioMedica for assistance with design and preparation of viral vectors. L.G.B. is a Wellcome Trust Prize student. L.G. is the Graham Watts Senior Research Fellow funded by the Brain Research Trust. This work was funded by Oxford Biomedica Ltd.

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Authors and Affiliations

  1. Oxford Biomedica (UK) Ltd, Medawar Centre, The Oxford Science Park, Oxford, OX4 4GA, UK

    G Scott Ralph, Pippa A Radcliffe, Denise M Day, Janine M Carthy, Marie A Leroux, Debbie C P Lee, Liang-Fong Wong, Susan M Kingsman, Kyriacos A Mitrophanous, Nicholas D Mazarakis & Mimoun Azzouz

  2. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Lynsey G Bilsland & Linda Greensmith

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  1. G Scott Ralph
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Correspondence to G Scott Ralph or Mimoun Azzouz.

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Competing interests

The authors GSR, PAR, DMD, JMM, MAL, LFW, SMK, KAM, NDM, and MA are share holders in Oxford Biomedica (UK) Ltd and as such have competing financial interests in the publication of this work.

Supplementary information

Supplementary Fig. 1

Analysis of transgene copy number in EIAV-injected SOD1G93A mice used for this study. (PDF 60 kb)

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Ralph, G., Radcliffe, P., Day, D. et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med 11, 429–433 (2005). https://doi.org/10.1038/nm1205

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