Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives

There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The chall...

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Autores principales:	Chiara Pisciotta, Paola Saveri, Davide Pareyson
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	CMT therapy management clinical trials gene therapy gene silencing Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/26df246002704957a7322e773f9686f8
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spelling	oai:doaj.org-article:26df246002704957a7322e773f9686f82021-11-25T16:57:36ZChallenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives10.3390/brainsci111114472076-3425https://doaj.org/article/26df246002704957a7322e773f9686f82021-10-01T00:00:00Zhttps://www.mdpi.com/2076-3425/11/11/1447https://doaj.org/toc/2076-3425There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing, to counteract the <i>PMP22</i> gene overexpression in the most frequent CMT1A type are under investigation. PXT3003 is the compound in the most advanced phase for CMT1A, as a second-phase III trial is ongoing. Gene therapy to substitute defective genes or insert novel ones and compounds acting on pathways important for different CMT types are being developed and tested in animal models. Modulation of the Neuregulin pathway determining myelin thickness is promising for both hypo-demyelinating and hypermyelinating neuropathies; intervention on Unfolded Protein Response seems effective for rescuing misfolded myelin proteins such as P0 in CMT1B. HDAC6 inhibitors improved axonal transport and ameliorated phenotypes in different CMT models. Other potential therapeutic strategies include targeting macrophages, lipid metabolism, and Nav1.8 sodium channel in demyelinating CMT and the P2X7 receptor, which regulates calcium influx into Schwann cells, in CMT1A. Further approaches are aimed at correcting metabolic abnormalities, including the accumulation of sorbitol caused by biallelic mutations in the sorbitol dehydrogenase (<i>SORD</i>) gene and of neurotoxic glycosphingolipids in HSN1.Chiara PisciottaPaola SaveriDavide PareysonMDPI AGarticleCMTtherapymanagementclinical trialsgene therapygene silencingNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENBrain Sciences, Vol 11, Iss 1447, p 1447 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CMT therapy management clinical trials gene therapy gene silencing Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	CMT therapy management clinical trials gene therapy gene silencing Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Chiara Pisciotta Paola Saveri Davide Pareyson Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives
description	There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing, to counteract the <i>PMP22</i> gene overexpression in the most frequent CMT1A type are under investigation. PXT3003 is the compound in the most advanced phase for CMT1A, as a second-phase III trial is ongoing. Gene therapy to substitute defective genes or insert novel ones and compounds acting on pathways important for different CMT types are being developed and tested in animal models. Modulation of the Neuregulin pathway determining myelin thickness is promising for both hypo-demyelinating and hypermyelinating neuropathies; intervention on Unfolded Protein Response seems effective for rescuing misfolded myelin proteins such as P0 in CMT1B. HDAC6 inhibitors improved axonal transport and ameliorated phenotypes in different CMT models. Other potential therapeutic strategies include targeting macrophages, lipid metabolism, and Nav1.8 sodium channel in demyelinating CMT and the P2X7 receptor, which regulates calcium influx into Schwann cells, in CMT1A. Further approaches are aimed at correcting metabolic abnormalities, including the accumulation of sorbitol caused by biallelic mutations in the sorbitol dehydrogenase (<i>SORD</i>) gene and of neurotoxic glycosphingolipids in HSN1.
format	article
author	Chiara Pisciotta Paola Saveri Davide Pareyson
author_facet	Chiara Pisciotta Paola Saveri Davide Pareyson
author_sort	Chiara Pisciotta
title	Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives
title_short	Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives
title_full	Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives
title_fullStr	Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives
title_full_unstemmed	Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives
title_sort	challenges in treating charcot-marie-tooth disease and related neuropathies: current management and future perspectives
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/26df246002704957a7322e773f9686f8
work_keys_str_mv	AT chiarapisciotta challengesintreatingcharcotmarietoothdiseaseandrelatedneuropathiescurrentmanagementandfutureperspectives AT paolasaveri challengesintreatingcharcotmarietoothdiseaseandrelatedneuropathiescurrentmanagementandfutureperspectives AT davidepareyson challengesintreatingcharcotmarietoothdiseaseandrelatedneuropathiescurrentmanagementandfutureperspectives
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Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives

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