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From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis

Nature Genetics volume 42, pages 392399 (2010) | Download Citation

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Using unbiased transcript profiling in an ALS mouse model, we identified a role for the co-stimulatory pathway, a key regulator of immune responses. Furthermore, we observed that this pathway is upregulated in the blood of 56% of human patients with ALS. A therapy using a monoclonal antibody to CD40L was developed that slows weight loss, delays paralysis and extends survival in an ALS mouse model. This work demonstrates that unbiased transcript profiling can identify cellular pathways responsive to therapeutic intervention in a preclinical model of human disease.

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Acknowledgements

We thank S. Appel, J. McCoy, S. Hesterlee and R. Goldstein for their thoughtful scientific discussions and contributions, R. Puchalski and the staff of the Allen Institute for Brain Science for the contribution of the in situ hybridization data, S.F. Scott, who lost his battle with ALS in 2009, for establishing the rigorous parameters required to test therapeutics in the SOD1G93A model, J. Heywood and his family for establishing ALS TDI and continuing to support our efforts and A. Nieto and L. Nieto for their dedication and financial support for the development of therapeutics for ALS. This work was supported by the Muscular Dystrophy Association/Augie's Quest, the US Department of Defense, the RGK Foundation and all our patients with ALS and their families.

Author information

Author notes

    • John M Lincecum
    •  & Fernando G Vieira

    These authors contributed equally to this work.

Affiliations

  1. ALS Therapy Development Institute, Cambridge, Massachusetts, USA.

    • John M Lincecum
    • , Fernando G Vieira
    • , Monica Z Wang
    • , Kenneth Thompson
    • , Gerald S De Zutter
    • , Joshua Kidd
    • , Andrew Moreno
    • , Ricardo Sanchez
    • , Isarelis J Carrion
    • , Beth A Levine
    • , Bashar M Al-Nakhala
    • , Shawn M Sullivan
    • , Alan Gill
    •  & Steven Perrin

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Contributions

J.M.L., F.G.V., A.G. and S.P. designed the experiments. M.Z.W. performed the immunohistochemistry and FACS experiments. R.S. and I.J.C. performed the motor neuron histology. B.A.L. oversaw and consulted on the human blood sample study. K.T., J.K. and A.M. performed all the animal studies. G.S.D.Z. consulted on the interpretation of the results. B.M.A. and S.M.S. wrote the simulation and LIMS software. A.G. performed all pharmacological statistical analysis. S.P., J.M.L., A.G. and F.G.V. wrote the paper. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Steven Perrin.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3 and Supplementary Table 4

Excel files

  1. 1.

    Supplementary Table 1

    Calculated Q scores of significantly different pathways in SOD1G93A mice compared to non-transgenic littermates.

  2. 2.

    Supplementary Table 2

    RMA normalized gene expression data of all genes in five significantly changing pathways in SOD1G93A mice compared to non-transgenic littermates.

  3. 3.

    Supplementary Table 3

    Calculated fold-change data of all genes in five significantly changing pathways in SOD1G93A mice compared to non-transgenic littermates derived from RMA normalized data.

  4. 4.

    Supplementary Table 5

    Relative normalized transcript expression of costimulatory genes in human clinical blood samples.

  5. 5.

    Supplementary Note

    Clinical annotation of human clinical blood samples

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DOI

https://doi.org/10.1038/ng.557