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

2020 ◽  
Author(s):  
Benoit Gautier ◽  
Helene Hajjar ◽  
Sylvia Soares ◽  
Jade Berthelot ◽  
Marie Deck ◽  
...  
Keyword(s):  
Peripheral Nerves ◽  
Nerve Conduction Velocity ◽  
Viral Vector ◽  
Foot Drop ◽  
Sensory Impairment ◽  
Wild Type ◽  
Charcot Marie Tooth Disease ◽  
Potential Use ◽  
Tooth Disease

AbstractCharcot-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.

scholarly journals AAV2/9-mediated silencing of PMP22 prevents the development of pathological features in a rat model of Charcot-Marie-Tooth disease 1 A

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Benoit Gautier ◽  
Helene Hajjar ◽  
Sylvia Soares ◽  
Jade Berthelot ◽  
Marie Deck ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Rat Model ◽  
Viral Vector ◽  
Foot Drop ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Sensory Impairments ◽  
Potential Use ◽  
Tooth Disease ◽  
Bilateral Treatment

AbstractCharcot-Marie-Tooth disease 1 A (CMT1A) results from a duplication of the PMP22 gene in Schwann cells and a deficit of myelination in peripheral nerves. Patients with CMT1A have reduced nerve conduction velocity, muscle wasting, hand and foot deformations and foot drop walking. Here, we evaluate the safety and efficacy of recombinant adeno-associated viral vector serotype 9 (AAV2/9) expressing GFP and shRNAs targeting Pmp22 mRNA in animal models of Charcot-Marie-Tooth disease 1 A. Intra-nerve delivery of AAV2/9 in the sciatic nerve allowed widespread transgene expression in resident myelinating Schwann cells in mice, rats and non-human primates. A bilateral treatment restore expression levels of PMP22 comparable to wild-type conditions, resulting in increased myelination and prevention of motor and sensory impairments over a twelve-months period in a rat model of CMT1A. We observed limited off-target transduction and immune response using the intra-nerve delivery route. A combination of previously characterized human skin biomarkers is able to discriminate between treated and untreated animals, indicating their potential use as part of outcome measures.

Homozygous Expression of a Dominant Gene Causing Peroneal Muscular Atrophy (Charcot-Marie-Tooth Disease)

1974 ◽  
Vol 23 (S1) ◽  
pp. 217-220 ◽  
Author(s):  
H. Warner Kloepfer ◽  
James M. Killian
Keyword(s):  
Clinical Features ◽  
Nerve Conduction ◽  
Peripheral Nerves ◽  
Muscular Atrophy ◽  
Dominant Gene ◽  
Conduction Time ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Peroneal Muscular Atrophy ◽  
Tooth Disease

This study involves the presentation of a kindred from Southwestern Louisiana showing 66 individuals who were heterozygous for a rare dominant gene for a type of Charcot-Marie-Tooth disease with hypertrophy of peripheral nerves. Two marriages between heterozygotes resulted in the occurrence of five homozygous offsprings. Clinical features of these previously undescribed homozygotes are compared to the clinical features of the classic type of heterozygote. The value of using nerve-conduction time to detect the asymptomatic heterozygote for Charcot-Marie-Tooth disease is discussed.

scholarly journals Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations

2007 ◽  
Vol 176 (4) ◽  
pp. 405-414 ◽  
Author(s):  
Scott A. Detmer ◽  
David C. Chan
Keyword(s):  
Axonal Degeneration ◽  
Mitochondrial Protein ◽  
Mitochondrial Fusion ◽  
Wild Type ◽  
Cell Type ◽  
Charcot Marie Tooth Disease ◽  
Disease Mutations ◽  
Cell Type Specific ◽  
In Trans ◽  
Tooth Disease

Mfn2, an oligomeric mitochondrial protein important for mitochondrial fusion, is mutated in Charcot-Marie-Tooth disease (CMT) type 2A, a peripheral neuropathy characterized by axonal degeneration. In addition to homooligomeric complexes, Mfn2 also associates with Mfn1, but the functional significance of such heterooligomeric complexes is unknown. Also unknown is why Mfn2 mutations in CMT2A lead to cell type–specific defects given the widespread expression of Mfn2. In this study, we show that homooligomeric complexes formed by many Mfn2 disease mutants are nonfunctional for mitochondrial fusion. However, wild-type Mfn1 complements mutant Mfn2 through the formation of heterooligomeric complexes, including complexes that form in trans between mitochondria. Wild-type Mfn2 cannot complement the disease alleles. Our results highlight the functional importance of Mfn1–Mfn2 heterooligomeric complexes and the close interplay between the two mitofusins in the control of mitochondrial fusion. Furthermore, they suggest that tissues with low Mfn1 expression are vulnerable in CMT2A and that methods to increase Mfn1 expression in the peripheral nervous system would benefit CMT2A patients.

scholarly journals Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects.

1996 ◽  
Vol 7 (6) ◽  
pp. 907-916 ◽  
Author(s):  
Y Omori ◽  
M Mesnil ◽  
H Yamasaki
Keyword(s):  
Hela Cells ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Base Substitution ◽  
Cell Contact ◽  
Wild Type ◽  
Gap Junctional Intercellular Communication ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

We have characterized the function of connexin (Cx) 32 gene mutations found in X-linked dominant Charcot-Marie-Tooth disease with respect to their ability to form functional gap junctions among themselves and to inactivate wild-type Cx32 by a dominant negative mechanism. We prepared four types of Cx32 mutant cDNAs and transfected them into HeLa cells, which do not show detectable levels of gap junctional intercellular communication (GJIC), nor expression of any connexins examined. Cells transfected with the wild-type Cx32 gene, but not those transfected with three different base substitution mutations (i.e. Cys 60 to Phe, Val 139 to Met, and Arg 215 to Trp), restored GJIC. Unexpectedly, in cells transfected with a nonsense mutant at codon 220, there was also restored GJIC. When we double-transfected these mutant constructs into the HeLa cells that had already been transfected with the wild-type Cx32 gene and thus were GJIC proficient, three base substitution mutants inhibited GJIC, suggesting that these three mutants can eliminate the function of wild-type Cx32 in a dominant negative manner. The nonsense mutation at codon 220 did not show such a dominant negative effect. Since both mutant and wild-type Cx32 mRNAs were detected, but only poor Cx32 protein expression at cell-cell contact areas was observed in the double transfectants, it is suggested that certain mutants form nonfunctional chimeric connexons with wild-type connexins, which are not properly inserted into the cytoplasmic membrane.

Long term results of the revisited Meary closing wedge tarsectomy for the treatment of the fixed cavo-varus foot in adolescent with Charcot-Marie-Tooth disease

2019 ◽  
Vol 25 (6) ◽  
pp. 834-841 ◽  
Author(s):  
Anne-Laure Simon ◽  
Raphaël Seringe ◽  
Alina Badina ◽  
Nejib Khouri ◽  
Christophe Glorion ◽  
...  
Keyword(s):  
Long Term Results ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Closing Wedge ◽  
Tooth Disease

Long-Term Effective Thalamic Deep Brain Stimulation for Neuropathic Tremor in Two Patients with Charcot-Marie-Tooth Disease

2017 ◽  
Vol 95 (2) ◽  
pp. 102-106 ◽  
Author(s):  
Lidia Cabañes-Martínez ◽  
Marta Del Álamo de Pedro ◽  
Gema de Blas Beorlegui ◽  
Ignacio Regidor Bailly-Bailliere
Keyword(s):  
Deep Brain Stimulation ◽  
Brain Stimulation ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease ◽  
Deep Brain
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