Abstract
Charcot Marie Tooth diseases type 1A (CMT1A), caused by duplication of Peripheral Myelin Protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene are the two most common forms of demyelinating CMT (CMT1) and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modeled by MpzR98C/+ mice that also show ER-stress and an activated UPR. C3-PMP22 mice are considered to effectively model CMT1A. Altered proteostasis, ER-stress and activation of the UPR have been demonstrated in mice carrying Pmp22 mutations. To determine whether enabling the ER-stress/UPR and readjusting protein homeostasis would effectively treat these models of CMT1B and CMT1A we administered Sephin1/IFB-088/icerguestat, a UPR modulator which showed efficacy in the MpzS63del model of CMT1B, to heterozygous MpzR98C and C3-PMP22 mice. Mice were analyzed by behavioral, neurophysiological, morphological and biochemical measures. Both MpzR98C/+ and C3-PMP22 mice improved in motor function and neurophysiology. Myelination, as demonstrated by g-ratios and myelin thickness, improved in CMT1B and CMT1A mice and markers of UPR activation returned towards wild type values. Taken together our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT. Given the recent benefits of IFB-088 treatment in Amyotrophic Lateral Sclerosis and Multiple Sclerosis animal models, these data demonstrate its potential in managing UPR and ER-stress for multiple mutations in CMT1 as well as in other neurodegenerative diseases.
Competing Interest Statement
P.G., P.M. and C.T. are full-time employees and stockholders of InFlectis BioScience. M.D. acts as a Scientific Advisory Board member for InFlectis BioScience.
Footnotes
Author Emails:
Yunhong Bai yunhong-bai{at}uiowa.edu
Caroline Treins carolinetreins{at}inflectisbioscience.com
Vera G Volpi volpi.veragiulia{at}gmail.com
Cristina Scapin scapin33{at}gmail.com
Cinzia Ferri ferri.cinzia{at}hsr.it
Rosa Mastrangelo mastrangelo.rosa{at}hsr.it
Thierry Touvier touvier.thierry{at}hsr.it
Francesca Florio florio.francesca{at}hsr.it
Francesca Bianchi bianchi.francesca{at}hsr.it
Ubaldo Del Carro delcarro.ubaldo{at}hsr.it
Frank F Baas F.Baas{at}lumc.nl
David Wang david.wang2{at}uhhospitals.org
Pierre Miniou pierreminiou{at}inflectisbioscience.com
Philippe Guedat philippeguedat{at}inflectisbioscience.com
Michael E Shy michael-shy{at}uiowa.edu
Maurizio D’Antonio dantonio.maurizio{at}hsr.it
Abbreviations
- AD
- autosomal dominant
- AR
- autosomal recessive
- ASO
- anti-sense oligonucleotides
- ATF4
- activating transcription factor 4
- BiP
- immunoglobulin heavy chain-binding protein
- CHOP
- C/EBP homologous protein
- CMT
- Charcot Marie Tooth
- CMAP
- compound muscle action potential
- DRG
- dorsal root ganglia
- eIF2α
- alpha subunit of the eukaryotic translation initiation factor 2
- ER
- endoplasmic reticulum
- ERAD
- ER-associated degradation
- ERQC
- endoplasmic reticulum protein quality control
- Grp94
- glucose regulated protein 94
- IRE1
- inositol requiring enzyme 1
- MBP
- myelin binding protein
- MPZ
- myelin protein zero
- MNCV
- motor nerve conduction velocity
- NCV
- nerve conduction velocity
- NF
- neurofilament
- PERK
- protein-kinase RNA-like endoplasmic reticulum kinase
- PMP22
- peripheral myelin protein 22
- PND
- post-natal day
- PPP1R15A
- Protein Phosphatase 1 Regulatory Subunit 15A
- PQC
- protein quality control
- SNAP
- sensory nerve action potential
- SNCV
- sensory nerve conduction velocity
- UPR
- unfolded protein response
- TrJ
- Trembler J
- TEM
- transmission electron microscopy
- WB
- western blot
- WT
- wild type
- XBP1
- X-box-binding protein-1.