onapristone and Charcot-Marie-Tooth-Disease

Topics: Animals; Ascorbic Acid; Charcot-Marie-Tooth Disease; Connexins; Electrophysiology; Gap Junction beta-1 Protein; Gonanes; Hormone Antagonists; Humans; Mice; Myelin P0 Protein; Myelin Proteins; Peripheral Nervous System; Potassium Channels; Proteins; Rats

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy, and a duplication of the Pmp22 gene causes the most frequent subform CMT1A. Using a transgenic rat model of CMT1A, we tested the hypothesis that long-term treatment with anti-progesterone (Onapristone) reduces Pmp22 overexpression and improves CMT disease phenotype of older animals, thereby extending a previous proof-of-concept observation in a more clinically relevant setting.. We applied placebo-controlled progesterone-antagonist therapy to CMT rats for 5 months and performed grip-strength analysis to assess the motor phenotype. Quantitative Pmp22 RT-PCR and complete histological analysis of peripheral nerves and skin biopsies were performed.. Anti-progesterone therapy significantly increased muscle strength and muscle mass of CMT rats and reduced the performance difference to wildtype rats by about 50%. Physical improvements can be explained by the prevention of axon loss. Surprisingly, the effects of anti-progesterone were not reflected by improved myelin sheath thickness. Electrophysiology confirmed unaltered NCV, but less reduced CMAP recordings in the treatment group. Moreover, the reduction of Pmp22 mRNA, as quantified in cutaneous nerves, correlated with the clinical phenotype at later stages.. Progesterone-antagonist long-term therapy reduces [corrected] Pmp22 overexpression to a degree at which the axonal support function of Schwann cells is better maintained than myelination. This suggests that axonal loss in CMT1A is not caused by demyelination, but rather by a Schwann cell defect that has been partially uncoupled by anti-progesterone treatment. Pmp22 expression analysis in skin may provide a prognostic marker for disease severity and for monitoring future clinical trials.

Topics: Action Potentials; Age Factors; Animals; Animals, Genetically Modified; Animals, Newborn; Axons; Charcot-Marie-Tooth Disease; Demyelinating Diseases; Disease Models, Animal; Female; Gene Expression Regulation; Gonanes; Hormone Antagonists; Muscle, Skeletal; Myelin Proteins; Neural Conduction; Rats; Skin

Topics: Animals; Charcot-Marie-Tooth Disease; Gonanes; Hormone Antagonists; Humans; Myelin Proteins; Receptors, Progesterone

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.

Topics: Animals; Animals, Genetically Modified; Charcot-Marie-Tooth Disease; Disease Models, Animal; Gonanes; Hormone Antagonists; Humans; Myelin P0 Protein; Myelin Proteins; Progesterone; Rats; Receptors, Progesterone; RNA, Messenger

Topics: Animals; Charcot-Marie-Tooth Disease; Disease Models, Animal; Gonanes; Hormone Antagonists; Humans; Myelin Proteins; Rats