Table 1.
Summary of therapeutic strategies for demyelinating and dysmyelinating Charcot-Marie-Tooth disease
| Compound/Treatment strategy | CMT type | Mechanism | Studies |
|---|---|---|---|
| Phosphatidylcholine curcumin, Curcumin-cyclodextrin nanocrystals | CMT1A, CMT1B | ER-stress reduction and decreased UPR activation by sarcoplasmic/endoplasmic reticulum calcium pump inhibition | Patzkó et al., 2012; Caillaud et al., 2020 |
| Salubrinol, Sephin 1 | CMT1B | Inhibition of eIF2A dephosphorylation by GADD34 | D’Antonio et al., 2013; Das et al., 2015 |
| AAV2/9-mediated delivery of shRNA | CMT1A | Decreased PMP22 expression levels | Gautier et al., 2021 |
| AAV9-mediated delivery of GJB1 gene | CMT1X | Cx32 expression | Kagiava et al.,2021 |
| AAV1-mediated delivery of the Nt-3 gene | CMT1X | NT-3 expression | Ozes et al., 2022 |
| ASO | CMT1A | Reduction of PMP22 mRNA | Zhao et al., 2018 |
| siRNA conjugated to squalene nanoparticles | CMT1A | Reduction of PMP22 mRNA | Boutary et al., 2021 |
| CRISPR/Cas9 | CMT1A | Deletion of the TATA-box in PMP22 P1 promoter: reduction of PMP22 expression | Lee et al., 2020 |
| Theophylline | CMT1A | HDAC2 activation: increased P0 expression | Duman et al., 2020 |
| RGFP966 | CMT1A | HDAC3 inhibition: activation of PI3K/AKT and MEK/ERK signaling pathways and myelin protein expression | Prior et al., 2022 |
| CKD-504 | CMT1A | HDAC6 inhibition: decreased HSP90 acetylation and activation of the heat-shock pathway | Ha et al., 2020 |
| NVP-AUY922 | CMT1A | HSP90 inhibition: activation of the heat-shock pathway | Chittoor-Vinod et al., 2019 |
| BMS-561392 | CMT1B | TACE inhibition: NRG1-type III activation | Scapin et al., 2019 |
| rhNRG1 | CMT1A | Activation of PI3K/AKT pathway: improvement of PI3K/AKT and MEK/ERK imbalance | Fledrich et al., 2014 |
| PTX3003 (baclofen, naltrexone, and D-sorbitol) | CMT1A | Reduction of PMP22 mRNA: improvement of PI3K/AKT and MEK/ERK imbalance | Attarian et al., 2014; Chumakov et al., 2014; Prukop et al., 2019, 2020; Vita et al., 2019 |
| A438079 | CMT1A | Inhibition of P2X7 receptor: reduction of [Ca2+] in SCs | Sociali et al., 2016 |
| PLX5622 | CMT1B, CMT1X | Inhibition of CSF-1R: reduction of macrophage recruitment and activation | Klein et al., 2015 |
| Dietetary phosphatidylcholine and phosphatidylethanolamine supplementation | CMT1A | Stimulation of myelin biosynthesis | Fledrich et al., 2018 |
AAV: Adeno-associated viral vectors; ASO: antisense oligonucleotide; CMT1A: Charcot-Marie-Tooth disease type 1A; CMT1B: Charcot-Marie-Tooth type disease 1B; CMT1X: X-linked Charcot-Marie-Tooth disease type 1; CRISPR/Cas9: clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9; CSF-1R: colony-stimulating factor 1 receptor; Cx32: connexin 32; eIF2A: eukaryotic translation initiation factor 2A; ER: endoplasmic reticulum; GADD34: DNA damage inducible protein 34; GJB1: gap junction beta 1; HDAC2: histone deacetylase 2; HDAC3: histone deacetylase 3; HDAC6: histone deacetylase 6; HSP90: heat shock protein 90; MEK/ERK: extracellular signal-regulated kinase/mitogen-activated protein kinase; NRG1-type III: neuregulin 1 type III; NT-3: neurotropin-3; P0: myelin protein zero; PI3K/AKT: phosphoinositide-3 kinase/v-Akt murine thymoma viral oncogene homolog 1; PMP22: peripheral myelin protein 22; rhNRG1: recombinant human neuregulin 1; SERCA: sarcoplasmic/endoplasmic reticulum calcium pump; shRNA: short hairpin RNA; siRNA: small interfering RNA; TACE: tumor necrosis factor-alpha-converting enzyme; UPR: unfolded protein response.