Abstract
Advances in genetic technology and small molecule drug development have paved the way for clinical trials in Charcot-Marie-Tooth disease (CMT); however, the current FDA-approved clinical trial outcome measures are insensitive to detect a meaningful clinical response. There is, therefore, a need to identify sensitive outcome measures or clinically relevant biomarkers. The aim of this study was to further evaluate plasma neurofilament light chain (NFL) as a disease biomarker in CMT. Plasma NFL was measured using SIMOA technology in both a cross-sectional study of a US cohort of CMT patients and longitudinally over 6 years in a UK CMT cohort. In addition, plasma NFL was measured longitudinally in two mouse models of CMT2D. Plasma concentrations of NFL were increased in a US cohort of patients with CMT1B, CMT1X and CMT2A but not CMT2E compared with controls. In a separate UK cohort, over a 6-year interval, there was no significant change in plasma NFL concentration in CMT1A or HSN1, but a small but significant reduction in patients with CMT1X. Plasma NFL was increased in wild type compared to GARSC201R mice. There was no significant difference in plasma NFL in GARSP278KY compared to wild type mice. In patients with CMT1A, the small difference in cross-sectional NFL concentration vs healthy controls and the lack of change over time suggests that plasma NFL may lack sufficient sensitivity to detect a clinically meaningful treatment response in adulthood.
Highlights
Charcot-Marie-Tooth disease (CMT) is one of the commonest inherited neurological diseases with a population prevalence of 1 in 3000.1 With increased understanding of the genetic aetiology of CMT combined with advances in genetic therapies and small molecule drug development, the field is 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
We have previously demonstrated an increase in plasma neurofilament light chain (NFL) concentration in UK patients with CMT1A, CMT1X and HSN1.21 We, sought to see if we could replicate this finding in an independent cohort of patients with CMT from the United States of America
In contrast to our previous study in a UK cohort, there was no correlation between plasma NFL and the weighted Rasch modified CMT Examination Score (CMTES) and CMT neuropathy score (CMTNS) for any of the CMT subtypes included in the study (Figure 1B and Table 1)
Summary
Charcot-Marie-Tooth disease (CMT) is one of the commonest inherited neurological diseases with a population prevalence of 1 in 3000.1 With increased understanding of the genetic aetiology of CMT combined with advances in genetic therapies and small molecule drug development, the field is 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. CMT provides particular difficulties when it comes to designing clinical trials.[3] CMT is usually a lifelong disease, and even in the rapidly progressive forms, the rate of progression is slower than for other diseases such as amyotrophic lateral sclerosis. It is widely assumed that a successful treatment would be one that stops the progression of the disease, and clinical trials need to be designed with outcome measures that are able to detect a slowing in the rate of progression. A number of CMT-specific clinical outcome measures have been designed that have been validated or are undergoing validation, including the CMT neuropathy score, CMT Functional Outcome Measure, CMT Health Index and CMT Peds.[4,5,6,7,8,9] In addition, biomarkers of disease progression, such as nerve and muscle MRI are being developed as outcome measures for clinical trials.[10,11,12]
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