Experimental treatment with a new progesterone antagonist (Lonaprisan) in a PMP2

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(Oral presentation at the Antwerp Consortium July 2009)

Experimental treatment with a new progesterone antagonist (Lonaprisan) in a

PMP22transgenic rat model of Charcot-Marie-Tooth disease lA (CMT-IA).

B.G. Weiss1, R. Fledrich1, T. Prukop!, G. Meyer zu Horste3

, R. M. Stassart!, B.G. Brinkmannl, K.-A. Navel and M.W. Seredal,2

IMolecular and Translational Neurology, Department of Neurogenetics,

Max-Planck-Institute of Experimental Medicine, Gottingen, Germany; 2DepaItment

of Clinical Neurophysiology, University of G6ttingen, Germany; 'DepaItment of

Neurology, University of Diisseldorf, Germany

Charcot-Malie-Tooth disease (CMT) is the most common inherited neuropathy, and a

duplication of the PMP22 gene causes the most frequent subform, CMTIA,

Transgenic rats that overexpress Pmp22 mimic human CMTlA, and loweling Pmp22

expression by antiprogesterone

(Onapristone) ameliorates the neuropathic phenotype in young CMT rats within

weeks.

Onapristone is also beneficial when we extended this finding to adult CMT rats,

starting treatment at a later time point in order to better mimic the clinical

situation.

Unfortunately, Onapristone is known to have adverse side effects like liver

toxicity, so it is not possible to translate these findings into humans.

A new selective progesterone antagonist Lonaprisan (ZK230211 Schering, Gelmany)

is safe and used in Phase II clinical trial in breast cancer. We performed a

therapy trial over 7 weeks

in CMT rats to investigate the effect of Lonaprisan. At the end of the study,

animals were sacrificed and tissue was collected for histological and molecular

biological analysis.

Phenotype analysis (grip strength and bar test) was performed and revealed a

significant amelioration in motor performance beginning at 3,5 weeks of

treatment. Electrophysiological analysis revealed increased compound musle

action potentials (CMAP) in the treatment

group indicating prevention of axonal loss.

However, nerve conduction velocity (NCV) was unaltered after anti-progestin

treatment, similar to our findings in the previous study with Onapristone. We

suggest that Lonaprisan may be a well suited candidate drug to be used for

clinical trials in CMTlA patients.