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


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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Figure 1: Co-stimulatory pathway signaling in SOD1G93A skeletal muscle, spinal cord and sciatic nerve is upregulated during disease progression and is increased in a subset of blood samples from individuals with ALS.
Figure 2: Macrophages accumulate in peripheral nerves throughout the disease course.
Figure 3: Blocking CD40L with a monoclonal antibody to CD40L improves body-weight maintenance, delays disease onset and extends survival in SOD1 mice.
Figure 4: Meta-analysis of anti-CD40L treatment compared with riluzole, apocynin and historical controls.
Figure 5: MR1 treatment lowers the frequency of CD68+ cells in sciatic nerve and CD8+ T cells in sciatic lymph node.
Figure 6: Anti-CD40L treatment decreases astrocytosis and microgliosis while reducing motor neuron loss in the spinal cord of SOD1G93A mice.
Figure 7: Treatment of SOD1G93A mice with anti-CD40L decreases the expression of genes in the co-stimulatory pathway in the spinal cord.

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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




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.

Corresponding author

Correspondence to Steven Perrin.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Table 4 (PDF 3784 kb)

Supplementary Table 1

Calculated Q scores of significantly different pathways in SOD1G93A mice compared to non-transgenic littermates. (XLS 27 kb)

Supplementary Table 2

RMA normalized gene expression data of all genes in five significantly changing pathways in SOD1G93A mice compared to non-transgenic littermates. (XLS 735 kb)

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. (XLS 107 kb)

Supplementary Table 5

Relative normalized transcript expression of costimulatory genes in human clinical blood samples. (XLS 142 kb)

Supplementary Note

Clinical annotation of human clinical blood samples (XLS 69 kb)

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Lincecum, J., Vieira, F., Wang, M. et al. From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis. Nat Genet 42, 392–399 (2010).

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