Experimental therapy trials of the Carcot-Marie-Tooth Disease 1A in vivo

Charcot-Marie-Tooth Disease is the most common inherited demyelinating neuropathy of the peripheral nervous system. The most frequent subform is caused by an intrachromosomal du-plication, leading to toxic overexpression of the PMP22 gene (CMT1A). Transgenic rats overexpressing Pmp22 mimic typical features of the disease (`CMT rats´). Like in humans, a 1.6 fold Pmp22 overexpression leads to progressive demyelination with axonal loss causing distally pronounced muscle atrophy and weakness. Four experimental therapy trials of the Carcot-Marie-Tooth Disease 1A and one pilot experi-ment have been carried out. Treating the CMT rats with Lonaprisan lowered the Pmp22 overexpression and compared to Placebo treated animals the bar- and grip strength test showed an improved motor perform-ance, electrophysiological examinations revealed an increased compound muscle action po-tential, in peripheral nerves a preserved axonnumber and less macrophages were detected and in spinal cord cross sections a prevention of alpha-motoneuron loss could be observed. This implies neuroprotective properties of the progesterone antagonist in CMT1A. With the col-lected biological material a full range of ongoing experiments can be built on this study to lighten the underlying molecular mechanisms of this neuroprotection. With Igfbp5 a bio-marker (diagnostic marker) was established as an additional readout of a clinical trial next to the CMTNS. This marker could monitor the response to a therapy trial. In particular Curcumin has to be accentuated, because also in high dosages no adverse side effects were shown in patients. In the experimental therapy trial the reduced axonal loss im-pressed, compound muscle action potential and nerve conduction velocity were increased. To show also an improvement of the clinical phenotype that is not covered by a delayed gain of weight and thereby to pave the way for a translation to humans, a new experimental therapy trial with the increased bio-available Meriva Curcumin will be proposed. The neuroprotective properties of erythropoietin and the anti-inflammatory acting acetyl-salicylic acid achieved in the CMT rats no beneficial effect. With both substances the dosages, the treatment scheme and in case of acetylsalicylic acid also the choice of the anti-inflammatory substance need to be reconsidered. Promising and at the beginning of further investigation arise the liver x receptor (LXR) agonist T0901317 since it was able to reduce the Pmp22 overexpression. An experimental therapy trial would be the following step, but GW3965, another LXR agonist would be considered since it exhibited to have less adverse side effects on liver metabolism. With Lonaprisan and Curcumin new therapeutics sharing a striking effect on CMT1A have been introduced and need to be considered for a translation into humans.2014-03-1