Updated review of therapeutic strategies for Charcot-Marie-Tooth disease and related neuropathies

ABSTRACT

Introduction: Charcot–Marie–Tooth disease (CMT) and related neuropathies represent the most prevalent inherited neuromuscular disorders. Nonetheless, there is still no pharmacological treatment available for any CMT type. However, the landscape is rapidly evolving and several novel approaches are providing encouraging results in preclinical studies and leading to clinical trials.

Areas covered: The authors review the most promising therapies under study and the ongoing/planned clinical trials. Several approaches to address PMP22 overexpression underlying CMT1A, the most frequent subtype, are being tested. Gene silencing, targeting PMP22, and gene therapy, to introduce specific genes or to substitute or modulate defective ones, are being experimented in animal models. Compounds acting on ER stress, unfolded protein response, neuregulin pathways, phosphoinositides metabolism, axonal transport and degeneration, inflammation, polyol pathway, deoxysphingolipid metabolism, purine nucleotide pool are potential therapeutic candidates for different forms of CMT and related neuropathies.

Expert opinion: We are getting closer to find effective therapies for CMT, but are far behind the exciting examples of other genetic neuromuscular disorders. The authors analyze the possible reasons for this gap and the way to fill it. Preclinical and clinical research is ongoing with coordinated efforts and they are confident that in the next few years we will see the first effective treatments.

KEYWORDS:

• Axonal transport
• Charcot-Marie-Tooth disease
• clinical trials
• dHMN
• gene therapy
• Hsan
• management
• myelin
• outcome measures
• therapy

Article highlights

• Although Charcot-Marie-Tooth disease (CMT) and related neuropathies represent the most prevalent inherited neuromuscular disorders, there is still no drug treatment for any CMT type, and rehabilitation therapy as well as surgical correction of skeletal deformities are the only effective options available.

• CMT1A associated with the duplication and overexpression of PMP22 is the most frequent and most studied form, and several approaches to downregulate PMP22 have been developed. PXT3003 (a mixture of baclofen, sorbitol, and naloxone) showed interesting results and a novel phase III trial is starting; PMP22 gene silencing with ASO and siRNAs was effective in animal models and is under consideration for clinical trials.

• Promising approaches are represented by gene therapy to introduce neurotrophin-3 with a AAV1 vector for CMT1A and CMTX1, to replace defective gene via intrathecal delivery with lentiviral or AAV9 vectors for CMTX1 and CMT4C.

• Compounds modulating the unfolded protein response which is activated by several mutations in myelin genes are giving promising results in preclinical models and are candidate for clinical trials in CMT1A and CMT1B.

• Neuregulin molecules are determinant of myelin thickness and their modulation may be used to target both hypermyelinating neuropathies such as CMT4B and HNPP, and hypo- or dysmyelinating neuropathies, as confirmed in preclinical studies in rodents.

• Compounds preventing axonal degeneration or rescuing altered axonal transport have the potentiality to cure many hereditary neuropathies irrespective of the primary triggering defect: this is the case for the inhibitors of SARM1 and of HDAC6, an active field of research.

• Intervention on more specific metabolic pathways is also promising, such as for L-Serine to treat HSN1 by reducing neurotoxic deoxysphingolipids, or compounds acting on the PYKfive enzyme in the phosphoinositides metabolism in CMT4B, or S-adenosylmethionine (SAM) to supply purine nucleotides in CMTX5 and its allelic disorders.

• Mutations in sorbitol dehydrogenase has been very recently associated with a relatively common form of CMT2/dHMN and high levels of sorbitol. Inhibitors of aldose reductase, developed in the past for diabetic neuropathy, are good candidates for its treatment.

Declaration of interest

P Saveri declares travel grants from Kedrion. D Pareyson declares donations from Pfizer, LAM Therapeutics and Acceleron to support research activities of his Research Unit, financial support from Pfizer, Alnylam and Kedrion for participation in national and international meetings, participation in Advisory Board of Inflectis, Alnylam and Akcea, speaker honorarium from Alnylam. C Pisciotta, P Saveri, and D Pareyson are members of the Inherited Neuropathy Consortium RDCRN and of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.