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


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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Figure 1: CMT rats show interindividual variation in Pmp22 expression, muscle atrophy and clinical phenotype.
Figure 2: Progesterone modulates myelin gene expression in CMT rats.
Figure 3: Histopathology of progesterone- and onapristone-treated CMT rats.
Figure 4: Progesterone and onapristone modulate the disease phenotype of CMT rats.


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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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Correspondence to Klaus-Armin Nave.

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Sereda, M., Meyer zu Hörste, G., Suter, U. et al. Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med 9, 1533–1537 (2003).

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