Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice

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.

Hidden hearing loss in a Charcot-Marie-Tooth type 1A mouse model

“…The distinct AN myelin and axonal phenotypes in each CMT1 mouse model are also remarkably similar to those observed in other peripheral nerves, suggesting that the specific Pmp22 mutations exert common pathological effects across myelinating glia. For example, AN in CMT1A cochleas exhibit an increased proportion of smaller axons, a slight reduction in the number of myelinated fibers, hypermyelination of small diameter fibers, and a steepening of the regression line in the g-ratio vs axon diameter graph, all features that have been reported in other peripheral nerves of this mouse model and also in CMT1A rat models (44,(46)(47)(48). In contrast, sciatic nerves from CMT1E mice exhibit hypomyelination, much like what we and others have observed in the cochlea of this model (49)(50)(51).…”

“…3D, E). These results demonstrate that CMT1A and CMT1E mutations cause distinct AN axonal and myelin structural changes which are similar to those seen in other peripheral nerves (44,(46)(47)(48)(49)(50)(51), with CMT1A mice presenting a less severe phenotype.…”

Disrupting the transmembrane domain interface between PMP22 and MPZ causes peripheral neuropathy

“…A second question is whether complex formation with MPZ plays a pathogenic role in CMT, especially CMT1A that results from a gene duplication of PMP22 resulting in disease caused by mild over-expression of wildtype PMP22. One potential mechanism for the pathogenesis of CMT1A may be due to ER-stress from excess production of PMP22 (Bai et al, 2022;Hara et al, 2014;Marinko et al, 2020a;Pantera et al, 2020), that could be exacerbated by alteration of membrane morphology and perturbation of cholesterol distribution (Mittendorf et al, 2017;Zhou et al, 2020;Zhou et al, 2019). These effects would be mediated by simply too much PMP22 in the ER and motivates the therapeutic strategy of reducing PMP22 levels (Boutary et al, 2021).…”