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

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.

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

10.1101/2020.01.29.924605 ◽

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.

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Inverted formin 2-related Charcot-Marie-Tooth disease: extension of the mutational spectrum and pathological findings in Schwann cells and axons

Journal of the Peripheral Nervous System ◽

10.1111/jns.12106 ◽

2015 ◽

Vol 20 (1) ◽

pp. 52-59 ◽

Cited By ~ 17

Author(s):

Andreas Roos ◽

Joachim Weis ◽

Rudolf Korinthenberg ◽

Henry Fehrenbach ◽

Martin Häusler ◽

...

Keyword(s):

Schwann Cells ◽

Pathological Findings ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Mutational Spectrum ◽

Disease Extension ◽

Tooth Disease

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The α-chemokine CXCL14 is up-regulated in the sciatic nerve of a mouse model of Charcot–Marie–Tooth disease type 1A and alters myelin gene expression in cultured Schwann cells

Neurobiology of Disease ◽

10.1016/j.nbd.2008.11.014 ◽

2009 ◽

Vol 33 (3) ◽

pp. 448-458 ◽

Cited By ~ 15

Author(s):

Elena M. Barbaria ◽

Bianca Kohl ◽

Bettina A. Buhren ◽

Kerstin Hasenpusch-Theil ◽

Fabian Kruse ◽

...

Keyword(s):

Gene Expression ◽

Sciatic Nerve ◽

Mouse Model ◽

Schwann Cells ◽

Disease Type ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Cultured Schwann Cells ◽

Myelin Gene ◽

Tooth Disease

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CONNEXIN CHANNELS IN SCHWANN CELLS AND THE DEVELOPMENT OF THE X-LINKED FORM OF CHARCOT-MARIE-TOOTH DISEASE

Journal of the Peripheral Nervous System ◽

10.1046/j.1529-8027.2000.00022-42.x ◽

2000 ◽

Vol 5 (4) ◽

pp. 247-247

Author(s):

C Ressot ◽

R. Bruzzone

Keyword(s):

Schwann Cells ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Tooth Disease

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MicroRNAs as Biomarkers of Charcot-Marie-Tooth Disease Type 1A

Neurology ◽

10.1212/wnl.0000000000012266 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012266

Author(s):

Hongge Wang ◽

Matthew Davison ◽

Kathryn Wang ◽

Tai-he Xia ◽

Katherine M. Call ◽

...

Keyword(s):

Schwann Cell ◽

Schwann Cells ◽

Motor Nerve ◽

Disease Type ◽

Class Iii ◽

Protein Biomarkers ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Compound Muscle Action Potentials ◽

Tooth Disease

Objective:To determine if microRNA’s (miR) are elevated in the plasma of individuals affected by the inherited peripheral neuropathy Charcot-Marie-Tooth Disease, type 1A (CMT1A), miR profiling was employed to compare control and CMT1A plasma.Methods:We performed a screen of CMT1A and control plasma samples to identify miRs that are elevated in CMT1A using next generation sequencing, followed by validation of selected miRs by quantitative PCR, and correlation with protein biomarkers and clinical data: Rash-modified CMT Examination and Neuropathy Scores (CMTES-R and CMTNS-R), ulnar compound muscle action potentials (CMAP), and motor nerve conduction velocities (MNCV).Results:After an initial pilot screen, a broader screen confirmed elevated levels of several muscle-associated miRNAs (miR1, -133a, -133b, and -206, known as myomiRs) along with a set of miRs that are highly expressed in Schwann cells of peripheral nerve. Comparison to other candidate biomarkers for CMT1A (e.g. Neurofilament L, NfL) measured on the same sample set shows a comparable elevation of several miRs (e.g. miR133a, -206, -223) and ability to discriminate cases from controls. NfL levels were most highly correlated with miR133a. In addition, the putative Schwann cell miRs (e.g. miR223, -199a, -328, -409, and -431) correlate with the recently described TMPRSS5 protein biomarker that is most highly expressed in Schwann cells and also elevated in CMT1A plasma.Conclusions:These studies identify a set of miRs that are candidate biomarkers for clinical trials in CMT1A. Some of the miRs may reflect Schwann cell processes that underlie the pathogenesis of the disease.Classification of Evidence:This study provides Class III evidence that a set of plasma miRs are elevated in patients with CMT1A.

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Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

Journal of Experimental Medicine ◽

10.1084/jem.20122005 ◽

2013 ◽

Vol 210 (4) ◽

pp. 821-838 ◽

Cited By ~ 72

Author(s):

Maurizio D’Antonio ◽

Nicolò Musner ◽

Cristina Scapin ◽

Daniela Ungaro ◽

Ubaldo Del Carro ◽

...

Keyword(s):

Schwann Cells ◽

Therapeutic Strategy ◽

Terminal Differentiation ◽

Motor Deficit ◽

Demyelinating Neuropathy ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Unfolded Protein ◽

Protein Response ◽

Tooth Disease

P0 glycoprotein is an abundant product of terminal differentiation in myelinating Schwann cells. The mutant P0S63del causes Charcot-Marie-Tooth 1B neuropathy in humans, and a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum of Schwann cells, where it promotes unfolded protein stress and elicits an unfolded protein response (UPR) associated with translational attenuation. Ablation of Chop, a UPR mediator, from S63del mice completely rescues their motor deficit and reduces active demyelination by half. Here, we show that Gadd34 is a detrimental effector of CHOP that reactivates translation too aggressively in myelinating Schwann cells. Genetic or pharmacological limitation of Gadd34 function moderates translational reactivation, improves myelination in S63del nerves, and reduces accumulation of P0S63del in the ER. Resetting translational homeostasis may provide a therapeutic strategy in tissues impaired by misfolded proteins that are synthesized during terminal differentiation.

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