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BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Myotonic Dystrophy | Research article

Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood

Authors: Remco T. P. van Cruchten, Daniël van As, Jeffrey C. Glennon, Baziel G. M. van Engelen, Peter A. C. ‘t Hoen, the OPTIMISTIC consortium, the ReCognitION consortium

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Through a process of reverse engineering, this study aims to identify druggable molecular biomarkers associated with the clinical improvement in the OPTIMISTIC cohort.

Methods

Based on full blood samples collected during OPTIMISTIC, we performed paired mRNA sequencing for 27 patients before and after the CBT intervention. Linear mixed effect models were used to identify biomarkers associated with the disease-causing CTG expansion and the mean clinical improvement across all clinical outcome measures.

Results

We identified 608 genes for which their expression was significantly associated with the CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes associated with both returned to more normal levels in patients who benefited the most from CBT. This main finding has been replicated based on an external dataset of mRNA data of DM1 patients and controls, singling these genes out as candidate biomarkers for therapy response. Among these candidate genes were DNAJB12, HDAC5, and TRIM8, each belonging to a protein family that is being studied in the context of neurological disorders or muscular dystrophies. Across the different gene sets, gene pathway enrichment analysis revealed disease-relevant impaired signaling in, among others, insulin-, metabolism-, and immune-related pathways. Furthermore, evidence for shared dysregulations with another neuromuscular disease, Duchenne muscular dystrophy, was found, suggesting a partial overlap in blood-based gene dysregulation.

Conclusions

DM1-relevant disease signatures can be identified on a molecular level in peripheral blood, opening new avenues for drug discovery and therapy efficacy assessments.
Appendix
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Metadata
Title
Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood
Authors
Remco T. P. van Cruchten
Daniël van As
Jeffrey C. Glennon
Baziel G. M. van Engelen
Peter A. C. ‘t Hoen
the OPTIMISTIC consortium
the ReCognitION consortium
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02591-y

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