{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T17:34:17Z","timestamp":1772732057144,"version":"3.50.1"},"reference-count":60,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Charcot\u2013Marie\u2013Tooth disease (CMT) is the most frequent hereditary peripheral neuropathies. It is subdivided in two main groups, demyelinating (CMT1) and axonal (CMT2). CMT1 forms are the most frequent. The goal of this review is to present published data on 1\u2014cellular and animal models having opened new potential therapeutic approaches. 2\u2014exploration of these tracks, including clinical trials. The first conclusion is the great increase of publications on CMT1 subtypes since 2000. We discussed two points that should be considered in the therapeutic development toward a regulatory-approved therapy to be proposed to patients. The first point concerns long term safety if treatments will be a long-term process. The second point relates to the evaluation of treatment efficiency. Degradation of CMT clinical phenotype is not linear and progressive.<\/jats:p>","DOI":"10.3390\/ijms22136755","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T11:28:41Z","timestamp":1624447721000},"page":"6755","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Therapeutic Development in Charcot Marie Tooth Type 1 Disease"],"prefix":"10.3390","volume":"22","author":[{"given":"Pierre","family":"Miniou","sequence":"first","affiliation":[{"name":"InFlectis BioScience SAS, 21 Rue La Noue Bras de Fer, 44200 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel","family":"Fontes","sequence":"additional","affiliation":[{"name":"Centre de recherche en CardioVasculaire et Nutrition, Aix-Marseille Universit\u00e9, INRA 1260\u2014INSERM 1263, 13005 Marseille, France"},{"name":"Repositioning SAS, 8 Rue Napoleon, 20210 Calenzana, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/j.1399-0004.1974.tb00638.x","article-title":"Genetic and clinical aspects of Charcot-Marie-Tooth\u2019s disease","volume":"6","author":"Skre","year":"2008","journal-title":"Clin. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/ana.10089","article-title":"Charcot-Marie-Tooth disease and related neuropathies: Mutation distribution and genotype-phenotype correlation","volume":"51","author":"Boerkoel","year":"2002","journal-title":"Ann. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1136\/jnnp-2014-308826","article-title":"CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: A cross-sectional analysis","volume":"86","author":"Fridman","year":"2015","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0092-8674(91)90613-4","article-title":"DNA duplication associated with Charcot-Marie-Tooth disease type 1A","volume":"66","author":"Lupski","year":"1991","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/0960-8966(91)90055-W","article-title":"Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a)","volume":"1","author":"Raeymaekers","year":"1991","journal-title":"Neuromuscul. Disord."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/S0896-6273(00)80128-2","article-title":"A Transgenic Rat Model of Charcot-Marie-Tooth Disease","volume":"16","author":"Sereda","year":"1996","journal-title":"Neuron"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1093\/hmg\/5.5.563","article-title":"Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA","volume":"5","author":"Huxley","year":"1996","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1093\/hmg\/7.3.449","article-title":"Correlation between varying levels of PMP22 expression and the degree of demyelination and reduction in nerve conduction velocity in transgenic mice","volume":"7","author":"Huxley","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1097\/NEN.0b013e318217eba0","article-title":"Myelin and Axon Pathology in a Long-Term Study ofPMP22-Overexpressing Mice","volume":"70","author":"Verhamme","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1136\/jnnp.62.4.310","article-title":"Epidemiology of peripheral neuropathy","volume":"62","author":"Martyn","year":"1997","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1126\/science.8266101","article-title":"Connexin mutations in X-linked Charcot-Marie-Tooth disease","volume":"262","author":"Bergoffen","year":"1993","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1001\/archneur.60.4.605","article-title":"Transient, Recurrent, White Matter Lesions in X-linked Charcot-Marie-Tooth Disease With Novel Connexin 32 Mutation","volume":"60","author":"Hanemann","year":"2003","journal-title":"Arch. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8410","DOI":"10.1073\/pnas.88.19.8410","article-title":"Gap junctions formed by connexins 26 and 32 alone and in combination are differently affected by applied voltage","volume":"88","author":"Barrio","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S1043-4682(10)80003-0","article-title":"Molecular biology and genetics of gap junction channels","volume":"3","author":"Kumar","year":"1992","journal-title":"Semin. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4545","DOI":"10.1523\/JNEUROSCI.17-12-04545.1997","article-title":"Structural Abnormalities and Deficient Maintenance of Peripheral Nerve Myelin in Mice Lacking the Gap Junction Protein Connexin 32","volume":"17","author":"Anzini","year":"1997","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/(SICI)1098-1136(199809)24:1<8::AID-GLIA2>3.0.CO;2-3","article-title":"Connexin32-null mice develop demyelinating peripheral neuropathy","volume":"24","author":"Scherer","year":"1998","journal-title":"Glia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/glia.22279","article-title":"Connexin 32 is involved in mitosis","volume":"60","author":"Mones","year":"2011","journal-title":"Glia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1083\/jcb.200402087","article-title":"Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder","volume":"165","author":"Kobsar","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/ng1195-281","article-title":"Protein zero (P0)\u2013deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies","volume":"11","author":"Martini","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2358","DOI":"10.1523\/JNEUROSCI.3819-05.2006","article-title":"Different Intracellular Pathomechanisms Produce Diverse Myelin Protein Zero Neuropathies in Transgenic Mice","volume":"26","author":"Wrabetz","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1093\/brain\/aws140","article-title":"MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot\u2013Marie\u2013Tooth disease type 1B","volume":"135","author":"Saporta","year":"2012","journal-title":"Brain"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1093\/hmg\/ddy336","article-title":"A nonsense mutation in myelin protein zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function","volume":"28","author":"Fratta","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/acn3.543","article-title":"Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B","volume":"5","author":"Bai","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/ng1292-288","article-title":"Identical point mutations of PMP-22 in Trembler-J mouse and Char-cot-Marie-Tooth disease type 1A","volume":"2","author":"Valentijn","year":"1992","journal-title":"Nat. Genet."},{"key":"ref_25","first-page":"241","article-title":"Tayfun Trembler mouse carries a point mutation in a myelin gene","volume":"356","author":"Suter","year":"1992","journal-title":"Nat. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1006\/nbdi.2000.0323","article-title":"PMP22 Carrying the Trembler or Trembler-J Mutation Is Intracellularly Retained in Myelinating Schwann Cells","volume":"7","author":"Colby","year":"2000","journal-title":"Neurobiol. Dis."},{"key":"ref_27","first-page":"1765","article-title":"Progesterone Stimulates the Activity of the Promoters of Peripheral Myelin Protein-22 and Protein Zero Genes in Schwann Cells","volume":"71","author":"Thi","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0378-1119(00)00116-5","article-title":"Molecular dissection of the Schwann cell specific promoter of the PMP22 gene","volume":"248","author":"Sanguedolce","year":"2000","journal-title":"Gene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1038\/nm957","article-title":"Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A)","volume":"9","author":"Sereda","year":"2003","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1523\/JNEUROSCI.09-02-00625.1989","article-title":"Differentiation of axon-related Schwann cells in vitro: II. Control of myelin formation by basal lamina","volume":"9","author":"Eldridge","year":"1989","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/nm1023","article-title":"Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease","volume":"10","author":"Passage","year":"2004","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.nmd.2006.12.008","article-title":"Ascorbic acid inhibits PMP22 expression by reducing cAMP levels","volume":"17","author":"Kaya","year":"2007","journal-title":"Neuromuscul. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3614","DOI":"10.1016\/j.febslet.2008.09.040","article-title":"Ascorbic acid is a regulator of the intracellular cAMP concentration: Old molecule, new functions?","volume":"582","author":"Kaya","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/S1474-4422(09)70260-1","article-title":"Effect of ascorbic acid in patients with Charcot\u2013Marie\u2013Tooth disease type 1A: A multicentre, randomised, double-blind, placebo-controlled trial","volume":"8","author":"Micallef","year":"2009","journal-title":"Lancet Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S1474-4422(09)70108-5","article-title":"Ascorbic acid for Charcot\u2013Marie\u2013Tooth disease type 1A in children: A randomised, double-blind, placebo-controlled, safety and efficacy trial","volume":"8","author":"Burns","year":"2009","journal-title":"Lancet Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"17180","DOI":"10.1523\/JNEUROSCI.3457-11.2011","article-title":"Sodium-Dependent Vitamin C Transporter 2 Deficiency Causes Hypomyelination and Extracellular Matrix Defects in the Peripheral Nervous System","volume":"31","author":"Gess","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1002\/glia.23306","article-title":"Vitamin C promotes oligodendrocytes generation and remyelination","volume":"66","author":"Guo","year":"2018","journal-title":"Glia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13023-014-0201-x","article-title":"Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy","volume":"9","author":"Chumakov","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1186\/s13023-014-0199-0","article-title":"An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A","volume":"9","author":"Attarian","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.freeradbiomed.2020.09.019","article-title":"Curcumin\u2013cyclodextrin\/cellulose nanocrystals improve the phenotype of Charcot-Marie-Tooth-1A transgenic rats through the reduction of oxidative stress","volume":"161","author":"Caillaud","year":"2020","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1172\/JCI96499","article-title":"PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models","volume":"128","author":"Zhao","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_42","first-page":"130","article-title":"Targeted PMP22 TATA-box editing by CRISPR\/Cas9 reduces demyelinating neuropathy of Charcot-Marie-Tooth disease type 1A in mice","volume":"48","author":"Lee","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3528","DOI":"10.1093\/hmg\/ddz199","article-title":"Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X","volume":"28","author":"Kagiava","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1093\/hmg\/ddy056","article-title":"Intrathecal gene therapy in mouse models expressing CMT1X mutations","volume":"27","author":"Kagiava","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1126\/science.1065693","article-title":"Calcium, calmodulin, and CaMKII requirement for initiation of centrosome duplication in Xenopus egg extracts","volume":"295","author":"Matsumoto","year":"2002","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3389\/fnins.2014.00151","article-title":"CamKII inhibitors reduce mitotic instability, connexon anomalies and progression of the in vivo behavioral phenotype in transgenic animals expressing a mutated Gjb1 gene","volume":"8","author":"Mones","year":"2014","journal-title":"Front. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13023-015-0270-5","article-title":"CMTX1 patients\u2019 cells present genomic instability corrected by CamKII inhibitors","volume":"10","author":"Saleh","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Bihel, F., Gess, B., and Font\u00e9s, M. (2016). CMTX Disorder and CamKinase. Front. Cell. Neurosci., 10.","DOI":"10.3389\/fncel.2016.00049"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1086\/497541","article-title":"Curcumin Treatment Abrogates Endoplasmic Reticulum Retention and Aggregation-Induced Apoptosis Associated with Neuropathy-Causing Myelin Protein Zero\u2013Truncating Mutants","volume":"77","author":"Khajavi","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.nbd.2016.05.014","article-title":"Progression of motor axon dysfunction and ectopic Nav1.8 expression in a mouse model of Charcot-Marie-Tooth disease 1B","volume":"93","author":"Rosberg","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1093\/brain\/awq336","article-title":"Nav1.8 channelopathy in mutant mice deficient for myelin protein zero is detrimental to motor axons","volume":"134","author":"Moldovan","year":"2010","journal-title":"Brain"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.neulet.2016.08.019","article-title":"An oral Na V 1.8 blocker improves motor function in mice completely deficient of myelin protein P 0","volume":"632","author":"Rosberg","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1016\/j.clinph.2020.06.034","article-title":"Myelin protein zero gene dose dependent axonal ion-channel dysfunction in a family with Charcot-Marie-Tooth disease","volume":"131","author":"Moldovan","year":"2020","journal-title":"Clin. Neurophysiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1111\/j.1600-0854.2004.00232.x","article-title":"Pharmacologic Rescue of Conformationally-Defective Proteins: Implications for the Treatment of Human Disease","volume":"5","author":"Janovick","year":"2004","journal-title":"Traffic"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1126\/science.aaa4484","article-title":"Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit","volume":"348","author":"Das","year":"2015","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/glia.22899","article-title":"Neuroinflammation in the peripheral nerve: Cause, modulator, or bystander in peripheral neuropathies?","volume":"64","author":"Martini","year":"2016","journal-title":"Glia"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"11392","DOI":"10.1038\/s41598-019-47818-w","article-title":"Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease","volume":"9","author":"Pearsall","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1212\/01.WNL.0000171978.70849.c5","article-title":"NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients","volume":"65","author":"Sahenk","year":"2005","journal-title":"Neurology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"146533","DOI":"10.1016\/j.brainres.2019.146533","article-title":"Gene therapy to promote regeneration in Charcot-Marie-Tooth disease","volume":"1727","author":"Sahenk","year":"2020","journal-title":"Brain Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3025","DOI":"10.1038\/s41467-018-05420-0","article-title":"Targeting myelin lipid metabolism as a potential therapeutic strategy in a model of CMT1A neuropathy","volume":"9","author":"Fledrich","year":"2018","journal-title":"Nat. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6755\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:22:10Z","timestamp":1760163730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6755"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,23]]},"references-count":60,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22136755"],"URL":"https:\/\/doi.org\/10.3390\/ijms22136755","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,23]]}}}