Current Treatment Methods for Charcot-Marie-Tooth Diseases

Abstract

Charcot-Marie-Tooth (CMT) disease, the most common inherited neuromuscular disorder, exhibits a wide phenotypic range, genetic heterogeneity, and a variable disease course. The diverse molecular genetic mechanisms of CMT were discovered over the past three decades with the development of molecular biology and gene sequencing technologies. These methods have brought new options for CMT reclassification and led to an exciting era of treatment target discovery for this incurable disease. Currently, there are no approved disease management methods that can fully cure patients with CMT, and rehabilitation, orthotics, and surgery are the only available treatments to ameliorate symptoms. Considerable research attention has been given to disease-modifying therapies, including gene silencing, gene addition, and gene editing, but most treatments that reach clinical trials are drug treatments, while currently, only gene therapies for CMT2S have reached the clinical trial stage. In this review, we highlight the pathogenic mechanisms and therapeutic investigations of different subtypes of CMT, and promising therapeutic approaches are also discussed.

Keywords: Charcot–Marie–Tooth; drug therapy; gene therapy; pathomechanism; rehabilitation; surgery.

Figure 1

The typical clinical presentations of CMT patients. Claw hands and interosseous muscle atrophy; muscle atrophy of the anterior tibial, peroneal, and posterior tibial muscles; and bilateral pes cavus, i.e., hammertoes.

Figure 2

The molecular and genetic targets involving pathogenesis in CMT. The causal genes disturb functions of cellular processes, which are implicated in the pathogenesis of various types of CMT: cell member (MTMR2, FIG4), early endosomes (LITAF), endosomes (DNM2, SH3TC2, NDRG1), lysosome (LRSAM1), endoplasmic reticulum (PMP22, MPZ, JAG1), Golgi apparatus (GBF1, SPG11), mitochondria (MFN2, MPV17, GADP1, DHTKD1, VCP, SURF1, AIFM1, PRPS1, PDKS), DNA (PNKP, MED25, MORC2, PRX), transcription (EGR2, IGHMBP2), translation (NEFH, NEFL, GARS1, AARS1, TRIM2, MME, MARS1, HARS1, FGD4), nuclear envelope (LMNA), fatty acids (PMP2), and protein chaperone (HSPB1, HSPB8). The dysregulation of Schwann cell differentiation and proliferation leads to demyelination. Protein aggregation (NEFL, HSPB1), axonal transport deficits (KIF1B, DYNC1H1, RAB7, CADM3), and ion-channel (ATP1A1, SLC12A6) dysfunction have also been implicated in different types of CMT.

Figure 3

The RNAi technology in gene therapy for CMT. The Pri-miRNAs are transcribed by DNA-dependent RNA polymerase II (Pol II) transcriptional complex. After expression in the nucleus, Pri-shRNAs and Pri-miRNAs are processed by Drosha to Pre-shRNAs and Pre-miRNAs. Afterwards, both Pre-shRNAs and Pre-miRNAs are exported by Exportin-5 to the cytoplasm. The shRNAs and Pre-miRNAs are associated with Dicer, resulting in the removal of the loop sequence and synthesis siRNAs as well as miRNA. By targeting complementary sequence mRNAs, they construct into RISC, resulting in mRNAs degradation. The synthetic ASO combined with target mRNAs generates a DNA–RNA heteroduplex in cytoplasm, which is recognized by RNase H1 to cleave.