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Project

TOWARDS TRIAL READINESS IN HEREDITARY NEUROMUSCULAR DISEASES: Developing accurate, feasible and non-invasive outcome measures.

To evaluate the effect of a new treatment in clinical trials, we first need an adequate knowledge of the natural history of the disease in question, and a set of outcome measures to evaluate disease progression. Additionally, these outcome measures should be sensitive, reliable, objective, non-invasive and feasible. This thesis aims to improve trial readiness for three hereditary neuromuscular diseases: LGMDR12, BMD and SMA.

In chapter 1, we showed that Dixon PDFF imaging and Biodex® dynamometry of the thighs are sensitive outcome measures that can track disease progression in adults with LGMDR12 over the course of 1 year. We discovered that patients with a moderate baseline thigh muscle PDFF experienced a faster rate of muscle fat replacement on MRI and could therefore be selected for clinical trials to display a potential therapeutic effect with increased sensitivity. Additionally, we demonstrated that the PDFF analysis of an entire stack of Dixon MR images was superior to sampling single slices of thigh muscles, and we suggested that analysis of individual muscles could be better than muscle groups. Because such extensive PDFF analyses are not feasible, we trained a CNN to semi-automate muscle segmentation to mitigate this issue. In chapter 2, we applied 3D muscle segmentations from the iliac crest to the tibial plateau to detail the pattern of fat replacement in 18 thigh muscles in patients with LGMDR12. We discovered an inhomogeneous non-linear distribution of fat replacement in all examined muscles, which underscored the risk of sampling bias, and implied that muscle fat replacement in neuromuscular disorders cannot be assumed to occur homogeneously in thigh muscles. Based on all the results above, we postulated that 3D whole muscle segmentation for analysis of Dixon PDFF should become the benchmark method in quantitative MR imaging studies. Additionally, we showed that muscle PDFF correlated to muscle biopsy fat fraction and other histopathological findings in affected muscles of patients with LGMDR12. This provided further confirmation of the validity of Dixon MR imaging in LGMDR12. 

In chapter 3, we studied respiratory decline in adults with BMD and concluded that a more vigilant follow-up of respiratory function in non-ambulatory patients is warranted. In chapter 4, we showed that PDFF measurement by 3D analysis of entire thigh muscles could detect disease progression in adults with BMD after only 9 months of follow-up. Given that a matched control group also showed a slight increase in PDFF, we argued that this should be accounted for when interpreting the results of future clinical trials. Out of a wide range of additional outcome measures, we revealed that the ActivLim scale (a PROM), and the MFM-32 or NSAA were sensitive enough to capture disease progression over 9 months. In chapter 5, we evaluated the potential of MR elastography as an outcome measure in adults with BMD. First, we designed the necessary equipment for muscle MRE imaging. Next, we demonstrated that test-retest reliability of muscle MRE was strongly variable in a group of subjects with and without muscle diseases. In contrast, test-retest reliability of PDFF and muscle volume measurements with 3D segmentation models was excellent. Finally, we discovered that thigh muscle stiffness was significantly lower in adults with BMD than in matched healthy controls, but that stiffness did not change over 9 months of follow-up. We concluded that muscle MRE imaging in its current form is not reliable enough to be applied in clinical trials. 

In chapter 6, we showed that nusinersen is a safe and efficacious treatment for adults with SMA, with improvements in hand grip strength, hand motor function, and skeletal muscle strength as measured by the MRC sum score over 14 months of follow-up. In addition, we detailed the natural history of untreated adults with SMA retrospectively and compared this with the improvements measured under treatment with nusinersen. In chapter 7, we reported further clinical improvements after 22 months of follow-up in nusinersen-treated adults with SMA. Additionally, we analyzed neuroinflammatory and neurodegenerative biomarkers in CSF and serum. Although CHIT1 and pNfH levels in CSF changed significantly over 22 months of nusinersen treatment, this did not correlate to changes in clinical outcome measures. Despite these interesting findings, we could not yet propose a biochemical biomarker of disease progression for follow-up of treatment effect in adults with SMA. 

In conclusion, we advanced trial readiness for LGMDR12, BMD and SMA by describing the natural history of these diseases and examining outcome measures of disease progression. These results are important for the design and analysis of future clinical trials. Finally, we also demonstrated that nusinersen is a safe and efficacious treatment for adults with SMA.

Date:1 Oct 2019 →  1 Oct 2023
Keywords:Neuromuscular, Trial readiness, Neurological disease
Disciplines:Neurological and neuromuscular diseases
Project type:PhD project