Abstract
The most common type of Charcot-Marie-Tooth disease is caused by a duplication of PMP22 leading to dysmyelination, axonal loss and progressive muscle weakness (CMT1A). Currently, no approved therapy is available for CMT1A patients. A novel polytherapeutic proof-of-principle approach using PXT3003, a low-dose combination of baclofen, naltrexone and sorbitol, slowed disease progression after long-term dosing in adult Pmp22 transgenic rats, a known animal model of CMT1A. Here, we report an early postnatal, short-term treatment with PXT3003 in CMT1A rats that delays disease onset into adulthood. CMT1A rats were treated from postnatal day 6 to 18 with PXT3003. Behavioural, electrophysiological, histological and molecular analyses were performed until 12 weeks of age. Daily oral treatment for approximately 2 weeks ameliorated motor deficits of CMT1A rats reaching wildtype levels. Histologically, PXT3003 corrected the disturbed axon calibre distribution with a shift towards large motor axons. Despite dramatic clinical amelioration, only distal motor latencies were improved and correlated with phenotype performance. On the molecular level, PXT3003 reduced Pmp22 mRNA overexpression and improved the misbalanced downstream PI3K-AKT / MEK-ERK signalling pathway. The improved differentiation status of Schwann cells may have enabled better long-term axonal support function. We conclude that short-term treatment with PXT3003 during early development may partially prevent the clinical and molecular manifestations of CMT1A. Since PXT3003 has a strong safety profile and is currently undergoing a phase III trial in CMT1A patients, our results suggest that PXT3003 therapy may be a bona fide translatable therapy option for children and young adolescent patients suffering from CMT1A.
Highlights
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy with a prevalence over one in 2500 [1,2]
We previously demonstrated an early reduction of the phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K)-AKT murine thymoma viral oncogene homolog 1 (AKT) signaling in CMT1A rat sciatic nerves during early postnatal development which was followed by an increase of the mitogen-activated protein kinase 1 (MEK)–mitogen-activated protein kinase (ERK) at P6
No adverse effects were observed in the wildtype or CMT1A rats treated with PXT3003 with regard to the weight, phenotype, electrophysiological parameters, histological abnormalities and molecular biology
Summary
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy with a prevalence over one in 2500 [1,2]. With Generation sequencing over 90 genes were linked to CMT [3,4], of which the most common type (CMT1A, over 39%, [5,6] is caused by a duplication of the gene encoding for the peripheral myelin protein of 22 kDa (PMP22) [7,8,9]. Neither trials of exercise and orthosis, nor pharmacological such as oral administration of ascorbic acid showed beneficial effects in patients with CMT1A [17,20,21,22,23]. The early onset of the disease raises the question of an effective, in best-case a preventive therapy option for young CMT1A patients
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