Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A)
| Autor: | Daniel Cohen, Jan Stenzel, Magdalena Mroczek, Rodolphe Hajj, Serguei Nabirotchkin, Theresa Kungl, Klaus-Armin Nave, Julia Adam, Stephanie Wernick, Michael W. Sereda, Thomas Prukop, David Ewers |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Macroglial Cells Baclofen Neural Conduction Axonal loss Disease Nervous System Naltrexone Rats Sprague-Dawley Phosphatidylinositol 3-Kinases chemistry.chemical_compound Nerve Fibers 0302 clinical medicine Animal Cells Charcot-Marie-Tooth Disease Gene duplication Medicine and Health Sciences Sorbitol Axon Animal Management Neurons Mammals Muscle Weakness Multidisciplinary Nerves Axons Schwann cells Sciatic nerves Muscle electrophysiology Histology Animal performance Rats Eukaryota Agriculture Animal Models MAP Kinase Kinase Kinases 3. Good health Drug Combinations Bioassays and Physiological Analysis medicine.anatomical_structure Experimental Organism Systems Vertebrates Medicine Cellular Types Anatomy Rats Transgenic Muscle Electrophysiology Myelin Proteins Research Article Signal Transduction medicine.drug congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty MAP Kinase Signaling System Science Transgene Glial Cells Research and Analysis Methods Rodents Proof of Concept Study Sciatic Nerves 03 medical and health sciences Model Organisms Internal medicine medicine Animals Animal Performance business.industry Electrophysiological Techniques Organisms Biology and Life Sciences Cell Biology Disease Models Animal Electrophysiology 030104 developmental biology Endocrinology chemistry Cellular Neuroscience Amniotes Animal Studies Schwann Cells business Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery Neuroscience Demyelinating Diseases |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 1, p e0209752 (2019) PLoS One |
| ISSN: | 1932-6203 |
| Popis: | 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. peerReviewed |
| Databáze: | OpenAIRE |
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