onapristone-progesterone antagonist

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(Repost of abstract about the onapristone study)

Nature Medicine 2003 Dec;9(12):1533-7.

Therapeutic administration of progesterone antagonist in a model of

Charcot-Marie-Tooth disease (CMT-1A).

Sereda MW, Meyer zu Horste G, Suter U, Uzma N, Nave KA.

Max-Planck Institute of Experimental Medicine, Department of

Neurogenetics, Hermann-Rein-Str. 3, D-37075 Gottingen, Germany.

Charcot-Marie-Tooth disease (CMT) is the most common inherited

neuropathy. The predominant subtype, CMT-1A, accounts for more than

50% of all cases 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

rats. 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.