Table 1.
Main therapeutic approaches and compounds under study for Charcot-Marie-Tooth disease and related neuropathies.
| CMT Type | Compound/Approach | Mechanism of Action/Aim of Therapy | Clinical Trials Status and Comments |
|---|---|---|---|
| Ascorbic acid | Reduction of PMP22 expression by reducing cAMP levels | Phase III studies concluded; all failed to meet their primary endpoints and did not show a significant effect | |
| CMT1A | Progesterone antagonists/modulators: onapristone, ulapristal | Reduction of PMP22 synthesis | Onapristone: unacceptable side effects. Ulapristal: phase II trial conducted (n = 23 out of 45 planned). Results not available |
| PXT3003 (mix of low doses of baclofen, sorbitol and naltrexone) |
Inhibition of SCs proliferation and reduction of the synthesis of PMP22; baclofen, GABAB receptor modulator | PXT3003: phase II (n = 80) concluded. Phase III (n = 323) concluded but unblinding problems in the high-dose group. New Phase III requested by FDA and just started |
|
| CMT1A, CMT1E | Gene silencing (ASOs, siRNAs, shRNAs, sgRNAs—CRISPR/Cas9) |
Partial silencing of overexpressed (CMT1A) or mutated (CMT1E) PMP22 | Under consideration. Issues: targeting a sufficient number of SCs, obtaining a proper quantitative silencing to avoid risk of HNPP, long-life therapy |
| CMT1A, CMTX1, CMT4C | Gene therapy (e.g., AAV1-NT-3; GJB1 and SH3TC2 gene substitution) |
Gene insertion (NT-3 = neurotrophic action) or (GJB1, SH3TC2) substitution | NT-3: open trial (n = 3) planned for CMT1A Gene substitution: still in preclinical phases |
| CMT1A, CMT1B, CMT4B, HNPP |
Neuregulin pathways (particularly Neuregulin-1 III) |
Regulation of myelin thickness | Niacin-niaspan candidate for CMT4B and HNPP? |
| CMT1A, CMT1E, CMT1B | Curcumin, sephin-1 | UPR inhibition by attenuation of the IRE1 branch | Possible clinical trial in CMT1A/CMT1B |
| CMT | FLX-787 | Activation of TRPA1 and TRPV1 channels, for cramps | Phase II (n = 120) stopped for oral intolerability in a subset of patients |
| All CMT and related neuropathies | SARM1 inhibitors | Prevention of axonal degeneration | -- |
| CMT2F, dHMN2A, CMT2A, CMT2D, dHMN5 (and others?) | HDAC6 inhibitors | Reduction of microtubules acetylation, improvement of axonal transport | Under consideration |
| CMT1, CMTX1 | ACE-083 | Action on myostatin pathway | Phase I+II (n = 62 overall) trial did not produce significant clinical improvement. Planned phase III trial abandoned |
| CMT1A | P2X7 receptor modulators (e.g., A438079) |
Reduction of abnormal calcium influx into SCs | P2X 7 antagonist acceptable safety and tolerability in a previous phase II trial in rheumatoid arthritis |
| CMT1A, other CMT? | Dietary lipid supplementation | Dietary correction of defective myelin lipid biosynthesis | Trial with oral lecithin supplementation planned in Germany |
| CMT1B, other dysmyelinating CMT? | Sodium channel blockers | Blocking of Nav 1.8 channel | Lamotrigine could be a candidate compound |
| CMT1A, CMT1B, CMTX1 | CSF1R inhibitors | Decreased number and activity of macrophages in the nerve | -- |
| CMT4B1, CMT4B2 |
PIKfyve enzyme inhibitors | Inhibition of PIKfyve and decrease of PI3,5P2 levels | To be considered for CMT4B1 and CMT4B2 |
| HSN1 | L-Serine | Reduction of neurotoxic deoxysphingolipids | Phase II trial (n = 18) performed, primary endpoint not reached, but underpowered trial |
| CMTX5 and allelic disorders (Arts syndrome and DFNX1) | S-adenosylmethionine (SAM) | Purine nucleotides supply | Anecdotal report |
| CMT and dHMN associated with biallelic SORD mutations | Aldose reductase inhibitors | Inhibition of aldose reductase, the enzyme converting glucose into sorbitol | Under consideration |
AAV1-NT-3 = adeno-associated virus-mediated neurotrophin-3, ASOs = antisense oligonucleotide, cAMP = cyclic adenosine monophosphate, CMT = Charcot-Marie-Tooth disease, CRISPR/Cas9 = clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9, CSF1R = colony-stimulating factor 1 receptor, DFNX1 = X-linked deafness-1, FDA = Food and Drug Administration, GABAB = gamma-aminobutyric acid B receptor, HDAC6 = histone deacetylase 6, dHMN = distal hereditary motor neuropathy, HNPP = hereditary neuropathy with liability to pressure palsies, HSN = hereditary sensory neuropathy, IRE1 = inositol-requiring enzyme 1, PIKfyve = phosphatidylinositol 3-phosphate 5-kinase, SARM1 = sterile alpha and TIR motif containing 1, SCs = Schwann cells, sgRNAs = single guide RNAs, shRNAs = short hairpin RNAs, siRNAs = small interfering RNAs, TRPA1 = transient receptor potential cation channel, subfamily A, member 1, TRPV1 = transient receptor potential cation channel subfamily V member 1, UPR = unfolded protein response.