Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

Abstract

Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing a wide range of therapeutics, leading to an exciting era of finding treatments for this, until now, incurable group of diseases. Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing while several have also reached clinical trial stage. Some of the treatment approaches are disease-specific targeted to the unique disease mechanism of each CMT form, while other therapeutics target common pathways shared by several or all CMT types. As promising treatments reach the stage of clinical translation, optimal outcome measures, novel biomarkers and appropriate trial designs are crucial in order to facilitate successful testing and validation of novel treatments for CMT patients.

NAD+ Metabolism and Diseases with Motor Dysfunction

“…Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy, with a worldwide prevalence of 1:2500 people [110]. CMT is a diverse neuropathy with over 80 genes associated with the disease [111].…”

“…CMT is a diverse neuropathy with over 80 genes associated with the disease [111]. Symptoms typically present themselves in childhood and early adolescence but may not become apparent until adulthood [110]. CMT can be classified different ways: age of onset, demyelinating or axonal, and affected nerve type (motor, sensory, or both) [110].…”

“…Symptoms typically present themselves in childhood and early adolescence but may not become apparent until adulthood [110]. CMT can be classified different ways: age of onset, demyelinating or axonal, and affected nerve type (motor, sensory, or both) [110]. CMT has been observed since the 1800s, but despite this, there has not been considerable investigation into the potential of NAD + as a therapeutic remedy, though what has been performed suggests potential benefits.…”

A longitudinal and cross‐sectional study of plasma neurofilament light chain concentration in Charcot‐Marie‐Tooth disease

“…1 With increased understanding of the genetic aetiology of CMT combined with advances in genetic therapies and small molecule drug development, the field is now entering an era where there are a number of promising therapies in the pipeline. 2 Developing successful treatments in preclinical models of CMT is only part of the journey in delivering therapies to patients. For a treatment to be adopted in routine clinical practice, it will need to show efficacy in clinical trials.…”

The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection

“…Paclitaxel is a well characterized stabilizer of MT and known to antagonize the deteriorating effect of kainic acid 18 . Axonal degradation is a hallmark of many neurodegenerative diseases 16 and increasing the stability of MTs via drug treatment has been shown to be advantageous in protecting neuronal integrity 38,39 . Axon fragmentation following kainic acid treatment was assessed by immuno uorescence staining for β-III tubulin (Fig.…”