Charcot-Marie-Tooth: From Molecules to Therapy

Morena, Jonathan; Gupta, Anirudh; Hoyle, J. Chad

doi:10.3390/ijms20143419

Cited by 126 publications

(124 citation statements)

References 121 publications

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“…Indeed, early nerve defects and impairments already occur in young CMT1A rats [16,15,13]. This is consistent with the disease onset occurring in the first decade in 75% of CMT1A patients [40]. Moreover, the treatment of young CMT1A rats (P6 to P18) with soluble Neuregulin-1 was sufficient to halt disease progression at least until 9 weeks of age, while treatment of adult animals has only a limited impact on the disease [16].…”

Section: Discussionsupporting

confidence: 71%

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

Gautier¹,

Hajjar

Soares

et al. 2020

Preprint

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Charcot-Marie-Tooth disease 1A (CMT1A) results from a duplication of the PMP22 gene leading to an excess of PMP22, a deficit of myelination and an instability of the myelin sheath in peripheral nerves. Patients present with reduced nerve conduction velocity, muscle waste, hand and foot deformations and foot drop walking problems. As gene silencing therapy has been shown to be effective in other monogenic neurological disorders, we evaluated the safety and efficacy of recombinant adeno-associated viral vector serotype 9 (AAV2/9)-based gene therapy for CMT1A. AAV2/9-mediated delivery of eGFP and shRNAs targeting PMP22 mRNA in the sciatic nerve allowed widespread gene expression in myelinating Schwann cells in mouse, rat and nonhuman primate. The treatment restored wild-type PMP22 level, increased myelination and prevented motor and sensory impairment over 12 months in a rat model of CMT1A. Intra-nerve injection limited off-target transduction and immune response to barely detectable levels. A combination of previously characterized human skin biomarkers successfully discriminated treated animals from their untreated littermate controls indicating their potential use as part of outcome measures in future clinical trials. Our results support intra nerve injection of AAV2/9 as an effective strategy for the treatment of CMT1A as well as other demyelinating CMT diseases.

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Section: Discussionsupporting

confidence: 71%

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

Gautier¹,

Hajjar

Soares

et al. 2020

Preprint

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“…Despite numerous attempts, no single effective therapeutic for CMT disorders has been registered on the market to date. The vast majority of CMT subtypes and mutations in "common" CMT genes with no "classical" (or an unknown) pathogenic mechanism have not been the subject of research for therapeutic approaches [39]. This state is a result of major barriers to research-including diverse molecular mechanisms for most CMT subtypes (even for different mutations in the same gene)-a lack of knowledge relating to the pathophysiology of specific variants, a deficiency of good disease models, and problems with translating results from animal models into humans.…”

Section: Therapeutic Approaches For Charcot-marie-tooth Disordermentioning

confidence: 99%

A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases

Rzepnikowska

Kamińska

Kabzińska

et al. 2020

IJMS

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Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of yeast as a model system in which to study CMT diseases. We show how this single-cell organism may be used to discriminate between pathogenic variants, to uncover the mechanism of pathogenesis, and to discover new therapies for CMT disease.

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“…Charcot-Marie-Tooth disease (CMT) is an eponym for a large range of related neuropathies that occur with a prevalence of ;1:2500 in the human population (1,2). Patients with CMT suffer from a range of symptoms including impaired tendon reflexes, weakness of the distal musculature, abnormalities of the peripheral nerve axon and its adjacent myelin sheath, and, in severe cases, confinement to a wheelchair (1,(3)(4)(5). Over two-thirds of CMT cases result from mutations in the PMP22 gene, including the most common form of the disease, CMT1A (6).…”

mentioning

confidence: 99%

Direct relationship between increased expression and mistrafficking of the Charcot–Marie–Tooth–associated protein PMP22

Marinko

Carter

Sanders

2020

Journal of Biological Chemistry

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Charcot-Marie-Tooth disease (CMT) is a neuropathy of the peripheral nervous system that afflicts ~1:2500 people. The most common form of this disease (CMT1A, 1:4000) is associated with duplication of chromosome fragment 17p11.2-12, which results in a third wild-type PMP22 allele. In rodent models overexpressing the peripheral myelin protein 22 (PMP22) protein and in dermal fibroblasts from patients with CMT1A, PMP22 aggregates have been observed. This suggests that overexpression of PMP22 under CMT1A conditions overwhelms the endoplasmic reticulum (ER) quality control, leading to formation of cytotoxic aggregates. In this work, we used a single-cell flow-cytometry trafficking assay to quantitatively examine the relationship between PMP22 expression and trafficking efficiency in individual cells. We observed that as expression of wild-type or disease variants of PMP22 is increased, the amount of intracellular PMP22 increases to a greater extent than the amount of surface-trafficked protein. This was true for both transiently transfected cells as well as PMP22 stable expressing cells. Our results support the notion that overexpression of PMP22 in CMT1A leads to a disproportionate increase in misfolding and mis-trafficking of PMP22, which is likely a contributor to disease pathology and progression.

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Charcot-Marie-Tooth: From Molecules to Therapy

Cited by 126 publications

References 121 publications

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases

Direct relationship between increased expression and mistrafficking of the Charcot–Marie–Tooth–associated protein PMP22

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