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Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A)

Nature Medicine volume 9, pages 15331537 (2003) | Download Citation

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Abstract

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. The predominant subtype, CMT-1A, accounts for more than 50% of all cases1 and is associated with an interstitial chromosomal duplication of 17p12 (refs. 2,3). We have generated a model of CMT-1A by introducing extra copies of the responsible disease gene, Pmp22 (encoding the peripheral myelin protein of 22 kDa), into transgenic rats4. Here, we used this model to test whether progesterone, a regulator of the myelin genes Pmp22 and myelin protein zero (Mpz) in cultured Schwann cells, can modulate the progressive neuropathy caused by moderate overexpression of Pmp22. Male transgenic rats (n = 84) were randomly assigned into three treatment groups: progesterone, progesterone antagonist (onapristone) and placebo control. Daily administration of progesterone elevated the steady-state levels of Pmp22 and Mpz mRNA in the sciatic nerve, resulting in enhanced Schwann cell pathology and a more progressive clinical neuropathy. In contrast, administration of the selective progesterone receptor antagonist reduced overexpression of Pmp22 and improved the CMT phenotype, without obvious side effects, in wild-type or transgenic rats. Taken together, these data provide proof of principle that the progesterone receptor of myelin-forming Schwann cells is a promising pharmacological target for therapy of CMT-1A.

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Acknowledgements

We thank E. Nicksch, U. Bode and C. Stünkel for technical help; M.R. Schneider (Schering) for providing us with onapristone; C. Scheidt-Nave for statistical advice; J.R. Lupski for helpful comments on the manuscript; and members of the Nave lab for discussion. This work was supported by the Max-Planck Society and by grants from the European Union (to K.A.N.). U.S. was supported by the Swiss National Science Foundation and by the National Center for Competence in Research “Neural Plasticity and Repair”. M.W.S. was supported in part by the Departments of Clinical Neurophysiology and Neurology at the University of Göttingen.

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Author notes

    • Michael W Sereda
    •  & Gerd Meyer zu Hörste

    These authors contributed equally to this work.

Affiliations

  1. Max-Planck Institute of Experimental Medicine, Department of Neurogenetics, Hermann-Rein-Str. 3, D-37075 Göttingen, Germany.

    • Michael W Sereda
    • , Gerd Meyer zu Hörste
    • , Naureen Uzma
    •  & Klaus-Armin Nave
  2. Departments of Neurology and Clinical Neurophysiology, University of Göttingen, Robert-Koch Str. 40, D-37075 Göttingen, Germany.

    • Michael W Sereda
  3. Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH Hoenggerberg, 8093 Zürich, Switzerland.

    • Ueli Suter

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Klaus-Armin Nave.

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DOI

https://doi.org/10.1038/nm957