Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice

Bai, Yunhong; Treins, Caroline; Volpi, Vera; Scapin, Cristina; Ferri, Cinzia; Mastrangelo, R; Touvier, Thierry; Florio, Francesca; Bianchi, Francesca; Carro, Ubaldo Del; Baas, Frank; Wang, David; Miniou, Pierre; Guédat, Philippe; Shy, Michael E.; D’Antonio, Maurizio

doi:10.1007/s12035-022-02838-y

Cited by 24 publications

(21 citation statements)

References 76 publications

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“…AAT treatment of inflamed cells upregulates the UPR, which may attenuate pro-apoptotic signaling. Interestingly, UPR attenuation has recently been tested in a preclinical study of CMT1A mice, highlighting the importance of the UPR in the progression of the disease [20]. Moreover, in our in vitro experimental setting, the p53 pathway and genes related to ER stress (e.g., ATF3) were downregulated by AAT, suggesting that AAT may be involved in modulating these biological responses in CMT1A as well.…”

Section: Discussionmentioning

confidence: 74%

Alpha-1 Antitrypsin Reduces Disease Progression in a Mouse Model of Charcot-Marie-Tooth Type 1A: A Role for Decreased Inflammation and ADAM-17 Inhibition

Zhukovsky¹,

Silvano²,

Filloux³

et al. 2022

IJMS

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Charcot-Marie-Tooth disease type 1 (CMT1A) is a hereditary peripheral neuropathy for which there is no available therapy. Alpha-1 antitrypsin (AAT) is an abundant serine protease inhibitor with anti-inflammatory and immunomodulating properties. Here, we tested whether treatment with human AAT (hAAT) would have a therapeutic effect on CMT1A in a PMP22 transgenic mouse model. Our results show that hAAT significantly improved compound muscle action potential and histopathological features and decreased circulating IL-6 in CMT1A mice. We also investigated some of the possible underlying mechanisms in vitro. We confirmed that hAAT inhibits ADAM-17, a protease that has been implicated in blocking myelination. Furthermore, both hAAT and recombinant human AAT (rhAAT) were able to attenuate the activation of a macrophage/microglia cell line, markedly decreasing the activation of the MHC class II promoter and the expression of pro-inflammatory genes such as IL-1β and the endoplasmic reticulum (ER) stress marker ATF3. Taken together, our results demonstrate for the first time that hAAT is able to reduce the progression of CMT1A, possibly by dampening inflammation and by regulating ADAM-17. Given the already well-established safety profile of hAAT, specifically in AAT deficiency disease (AATD), we suggest that the findings of our study should be promptly investigated in CMT1A patients.

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Section: Discussionmentioning

confidence: 74%

Alpha-1 Antitrypsin Reduces Disease Progression in a Mouse Model of Charcot-Marie-Tooth Type 1A: A Role for Decreased Inflammation and ADAM-17 Inhibition

Zhukovsky¹,

Silvano²,

Filloux³

et al. 2022

IJMS

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“…The positive effect of ICE in an animal model of OPMD along with its lower adverse effects make of this drug a promising therapeutic molecule for future treatments of OPMD. ICE was also shown to improve neuronal function in neurodegenerative diseases, such as Charcot–Marie–Tooth disease and amyotrophic lateral sclerosis [ 54 , 80 ]. Therefore, this molecule has strong potential for pharmacological approaches to diseases involving ER stress.…”

Section: Discussionmentioning

confidence: 99%

The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response

et al. 2023

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Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease characterized by the progressive degeneration of specific muscles. OPMD is due to a mutation in the gene encoding poly(A) binding protein nuclear 1 (PABPN1) leading to a stretch of 11 to 18 alanines at N-terminus of the protein, instead of 10 alanines in the normal protein. This alanine tract extension induces the misfolding and aggregation of PABPN1 in muscle nuclei. Here, using Drosophila OPMD models, we show that the unfolded protein response (UPR) is activated in OPMD upon endoplasmic reticulum stress. Mutations in components of the PERK branch of the UPR reduce muscle degeneration and PABPN1 aggregation characteristic of the disease. We show that oral treatment of OPMD flies with Icerguastat (previously IFB-088), a Guanabenz acetate derivative that shows lower side effects, also decreases muscle degeneration and PABPN1 aggregation. Furthermore, the positive effect of Icerguastat depends on GADD34, a key component of the phosphatase complex in the PERK branch of the UPR. This study reveals a major contribution of the ER stress in OPMD pathogenesis and provides a proof-of-concept for Icerguastat interest in future pharmacological treatments of OPMD.

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“…Having two distinct CMT1B disease mechanisms mapping to different structural regions of lg MPZ helps rationalize why the severity of CMT1B does not strictly correlate with the extent of UPR activation (Bai et al, 2018). Recently an inhibitor (lFB-088, Sephin1) of the PP1c/PPP1R15A phosphatase complex which works to potentiate UPR has been used to successfully treat mice with CMT1B variants and is entering Phase 2 trials (Bai et al, 2022; Das et al, 2015). We suggest the efficacy of Sephin1 treatment may correlate best with destabilizing variants within the core of the lg MPZ domain vs variants on the surface of the lg MPZ that might cause mis-function via a different mechanism.…”

Section: Discussionmentioning

confidence: 99%

Structural context of homomeric interactions in the lg domain of the MPZ (P0) myelin adhesion protein and relation to Charcot-Marie-Tooth disease phenotype variants

Ptak¹,

Peterson²,

Hopkins³

et al. 2023

Preprint

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Mutations in Myelin Protein Zero (MPZ) account for 5% of Charcot–Marie–Tooth cases and can cause demyelinating or axonal phenotypes, reflecting the diverse roles of MPZ in Schwann cells. MPZ holds the apposing membranes of the myelin sheath together, with the adhesion role fulfilled by the extracellular Immunoglobulin-like domain (IgMPZ), which can oligomerize. Current knowledge for how the IgMPZ might form oligomeric assemblies involving 3 weakly-interacting interfaces has been extrapolated from a protein crystal structure in which individual rat IgMPZ subunits are packed together under artificial conditions. These interfaces include one that organizes the IgMPZ into tetramers, a 'dimer' interface that could link tetramers together, and a third hydrophobic interface that could mediate binding to lipid bilayers or the same hydrophobic surface on another IgMPZ domain. There are at present no data confirming whether the proposed IgMPZ interfaces actually mediate oligomerization in solution, whether they are required for the adhesion activity of MPZ, whether they are important for myelination, or whether their loss results in disease. We performed NMR and SAXS analysis of wild–type IgMPZ as well as mutant forms with amino-acid substitutions designed to interrupt its presumptive oligomerization interfaces. Here, we confirm the interface that mediates IgMPZ tetramerization, but find that dimerization is mediated by a distinct interface that has yet to be identified. We next correlated CMT phenotypes to subregions within IgMPZ tetramers. Axonal late-onset disease phenotypes (CMT2I/J) map to surface residues of IgMPZ proximal to the transmembrane domain. Early-onset demyelinating disease phenotypes (CMT1B/Dejerine–Sottas syndrome) map to two groups: one is described by variants that disrupt the stability of the Ig-fold itself and are largely located within the core of the Ig domain; whereas another describes a surface on the distal outer surface of IgMPZ tetramers. Computational docking studies predict that this latter disease-relevant subregion may mediate dimerization of IgMPZ tetramers.

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Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice

Cited by 24 publications

References 76 publications

Alpha-1 Antitrypsin Reduces Disease Progression in a Mouse Model of Charcot-Marie-Tooth Type 1A: A Role for Decreased Inflammation and ADAM-17 Inhibition

Alpha-1 Antitrypsin Reduces Disease Progression in a Mouse Model of Charcot-Marie-Tooth Type 1A: A Role for Decreased Inflammation and ADAM-17 Inhibition

The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response

Structural context of homomeric interactions in the lg domain of the MPZ (P0) myelin adhesion protein and relation to Charcot-Marie-Tooth disease phenotype variants

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