1. Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood
- Author
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van Cruchten, Remco, van As, Daniël, Glennon, Jeffrey, van Engelen, Baziel, Okkersen, K, Jimenez-Moreno, C, Wenninger, S, Daidj, F, Cumming, S, Littleford, R, Monckton, D, Lochmüller, H, Catt, M, Faber, C, Hapca, A, Donnan, P, Gorman, G, Bassez, G, Schoser, B, Knoop, H, Treweek, S, Wansink, Derick, Impens, Francis, Gabriels, Ralf, Claeys, Tine, Ravel-Chapuis, Aymeric, Jasmin, Bernard, Mahon, Niamh, Nieuwenhuis, Sylvia, Martens, Lennart, Novak, Petr, Furling, Denis, Baak, Arie, Gourdon, Genevieve, Mackenzie, Alex, Martinat, Cecile, Neault, Nafisa, Roos, Andreas, Duchesne, Elise, Salz, Renee, Thompson, Rachel, Baghdoyan, Sandrine, Varghese, Anu, Blom, Paul, Spendiff, Sally, Manta, Alexander, Medical Psychology, APH - Mental Health, Radboud University Medical Center [Nijmegen], University College Dublin [Dublin] (UCD), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Newcastle University [Newcastle], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Universiteit Gent = Ghent University [Belgium] (UGENT), Centre de recherche en Myologie – U974 SU-INSERM, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
- Subjects
Lifestyle intervention ,Myotonic dystrophy type 1 ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Therapeutic Response ,Gene Expression ,Peripheral blood ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Nerve Tissue Proteins ,General Medicine ,Biomarker ,HSP40 Heat-Shock Proteins ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,All institutes and research themes of the Radboud University Medical Center ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Humans ,Myotonic Dystrophy ,RNA, Messenger ,RNA-seq ,Carrier Proteins ,Trinucleotide Repeat Expansion ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] - 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.
- Published
- 2022