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Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS

Nature Medicine volume 11, pages 423–428 (2005)Cite this article

Abstract

Mutations in Cu/Zn superoxide dismutase (encoded by SOD1), one of the causes of familial amyotrophic lateral sclerosis (ALS), lead to progressive death of motoneurons through a gain-of-function mechanism. RNA interference (RNAi) mediated by viral vectors allows for long-term reduction in gene expression and represents an attractive therapeutic approach for genetic diseases characterized by acquired toxic properties. We report that in SOD1G93A transgenic mice, a model for familial ALS, intraspinal injection of a lentiviral vector that produces RNAi-mediated silencing of SOD1 substantially retards both the onset and the progression rate of the disease.

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Figure 1: Lentiviral-mediated silencing of SOD1.
Figure 2: Lentiviral-mediated silencing of mutant SOD1 improves motor function in ALS mice.
Figure 3: Neuroprotective effective of lentiviral-mediated silencing of mutant SOD1.

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Acknowledgements

We acknowledge P. Colin, F. Pidoux, A. Maillard, C. Sadeghi and V. Padrun for their technical assistance. We are grateful to N. Déglon and W. Pralong for their critical comments throughout this work. We specially thank J. Iovanna for biosafety level 2 laboratory accommodation at Marseille. This work was supported by the ALS Association (ALSA), the Swiss National Science Foundation and the European Union contract LSHM-CT-2003-503330 (APOPIS).

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Authors and Affiliations

  1. Integrative Biosciences Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland

    Cédric Raoul, Toufik Abbas-Terki, Jean-Charles Bensadoun, Sandrine Guillot, Jolanta Szulc & Patrick Aebischer

  2. Avenir team, INSERM U29, INMED, Luminy, Marseille, 13273 cedex 09, France

    Georg Haase

  3. INSERM UMR 623, Developmental Biology Institute of Marseille (IBDM), Luminy, Marseille, 13288 cedex 09, France

    Christopher E Henderson

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  1. Cédric Raoul
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Correspondence to Patrick Aebischer.

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Supplementary information

Supplementary Fig. 1

Key components of the motoneuron cell death machinery are not modified by LV-shSOD1. (PDF 2665 kb)

Supplementary Fig. 2

LV-shSOD1 does not change the expression level of endogenous SOD1 in SOD1G93A transgenic mice. (PDF 1432 kb)

Supplementary Fig. 3

Gene replacement strategy for pan-silencing therapeutic strategy. (GIF 212 kb)

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Raoul, C., Abbas-Terki, T., Bensadoun, JC. et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nat Med 11, 423–428 (2005). https://doi.org/10.1038/nm1207

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