Recent advances in the treatment of Charcot‐Marie‐Tooth neuropathies

Abstract

Charcot‐Marie‐Tooth (CMT) neuropathies are one of the most common neuromuscular disorders. However, despite the identification of more than 100 causative genes, therapeutic options are still missing. The generation of authentic animal models and the increasing insights into the understanding of disease mechanisms, in addition to extraordinary developments in gene and molecular therapies, are quickly changing this scenario, and several strategies are currently being translated, or are getting close to, clinical trials. Here, we provide an overview of the most recent advances for the therapy of CMT at both the preclinical and clinical levels. For clarity, we have grouped the approaches in three different categories: gene therapy based on viral‐mediated delivery, molecular therapies based on alternative delivery systems, and pharmacological therapies.

Molecular mechanisms and therapeutic strategies for neuromuscular diseases

“…Of note, at least 120 responsible genes have been identified thus far, which encode a huge variety of proteins including structural proteins of the myelin, of the axonal cytoskeleton, transcription factors, regulators of intracellular trafficking, of mitochondrial function, of protein synthesis or homeostasis, and ion channels [ 84 ]. In the last three decades, in addition to advances in the clinical and genetic definition of the different forms, preclinical research has made significant progresses with the generation and characterization of animal and cellular models established from human iPSCs, which have been instrumental to study pathogenetic mechanisms and validate the effectiveness of therapeutic strategies [ 85 – 87 ]. Thus, even if no therapies are available to date for CMT patients, in the last few years numerous therapeutic strategies have been tested at preclinical level, some of which translated at clinical stage in phase 1–3 [ 85 ].…”

“…In the last three decades, in addition to advances in the clinical and genetic definition of the different forms, preclinical research has made significant progresses with the generation and characterization of animal and cellular models established from human iPSCs, which have been instrumental to study pathogenetic mechanisms and validate the effectiveness of therapeutic strategies [ 85 – 87 ]. Thus, even if no therapies are available to date for CMT patients, in the last few years numerous therapeutic strategies have been tested at preclinical level, some of which translated at clinical stage in phase 1–3 [ 85 ]. In this paragraph, we will provide an overview of these strategies and we will finally focus on the CMT1A neuropathy, due to the PMP22 gene duplication, the most frequent mutation in CMT that accounts for 50–60% of all CMTs.…”

Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B

“…The modulation of protein quality control systems represents an appealing therapeutic candidate in CMT1 disorders characterized by the accumulation of misfolded protein. 65 Curcumin, a low affinity SERCA inhibitor, has been shown to improve the trafficking of mutant proteins and reduce UPR markers in models of CMT1E and 1B. 66,67 More recently, the direct modulation of UPR pathways was demonstrated to be effective in the amelioration of both CMT1B and CMT1A mice.…”

Parent‐proxy pediatric CMT quality of life outcome measure: Validation of the Italian version

“…3 Despite extensive preclinical and clinical research, there is currently no specific disease-modifying treatment available for any of the different forms of CMT. 4,5 As an early intervention to prevent major axonal loss is more likely to be effective, a great deal of interest has been focused on treatments in the pediatric age group. 6 Therefore, validated endpoints specific for childhood CMT able to estimate the disease progression and response to therapy, including patient-reported outcome (PROs) measures, are clearly needed.…”

“…Functional and clinical impairment are often already evident during childhood, with varying degrees of disability and impact on quality of life (QOL) 3 . Despite extensive preclinical and clinical research, there is currently no specific disease‐modifying treatment available for any of the different forms of CMT 4,5 . As an early intervention to prevent major axonal loss is more likely to be effective, a great deal of interest has been focused on treatments in the pediatric age group 6 .…”