TY - JOUR
T1 - Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood
AU - van Cruchten, Remco T.P.
AU - van As, Daniël
AU - Glennon, Jeffrey C.
AU - van Engelen, Baziel G.M.
AU - ‘t Hoen, Peter A.C.
AU - Okkersen, K.
AU - Jimenez-Moreno, C.
AU - Wenninger, S.
AU - Daidj, F.
AU - Cumming, S.
AU - Littleford, R.
AU - Monckton, D. G.
AU - Lochmüller, H.
AU - Catt, M.
AU - Faber, C. G.
AU - Hapca, A.
AU - Donnan, P. T.
AU - Gorman, G.
AU - Bassez, G.
AU - Schoser, B.
AU - Knoop, H.
AU - Treweek, S.
AU - Wansink, Derick G.
AU - Impens, Francis
AU - Gabriels, Ralf
AU - Claeys, Tine
AU - Ravel-Chapuis, Aymeric
AU - Jasmin, Bernard J.
AU - Mahon, Niamh
AU - Nieuwenhuis, Sylvia
AU - Martens, Lennart
AU - Novak, Petr
AU - Furling, Denis
AU - Baak, Arie
AU - Gourdon, Genevieve
AU - MacKenzie, Alex
AU - Martinat, Cecile
AU - Neault, Nafisa
AU - Roos, Andreas
AU - Duchesne, Elise
AU - Salz, Renee
AU - Thompson, Rachel
AU - Baghdoyan, Sandrine
AU - Varghese, Anu Mary
AU - Blom, Paul
AU - Spendiff, Sally
AU - Manta, Alexander
N1 - Funding Information:
R. van Cruchten reports no disclosures relevant to the manuscript; D. van As reports no disclosures relevant to the manuscript; J.C. Glennon reports no disclosures relevant to the manuscript; B. G. M. van Engelen received fees (to the institution) and non-financial support from Fulcrum Therapeutics, Facio Therapies, and Arrowhead Pharmaceuticals during the conduct of the study. In addition, he received grant support from the FP7 European Union grand OPTIMISTIC, Marigold Foundation Canada, Prinses Beartrix Spierfonds, Spieren voor Spieren, FSHD Stichting, and FSHD Society. He also has an unpaid function as the head of the scientific advisory board for Euro-DyMA. P. A. C. ’t Hoen reports no disclosures relevant to the manuscript.
Funding Information:
This study was funded by the European Union’s Horizon 2020 research and innovation program “ERA-NET rare disease research implementing IRDiRC objectives - N° 643578” via the Dutch research funding agency ZON-MW, through the E-Rare Joint Transnational Call JTC 2018 “Translational Research Projects on Rare Diseases” (ReCognitION project: Recognition and validation of druggable targets from the response to Cognitive Behavior Therapy in Myotonic Dystrophy type 1 patients from integrated -omics networks). This study was also partially funded by the European Union Seventh Framework Program, under grant agreement no. 305697 (the Observational Prolonged Trial In Myotonic dystrophy type 1 to Improve Quality of Life Standards, a Target Identification Collaboration [OPTIMISTIC] project).
Funding Information:
We are grateful to the Newcastle MRC Centre for Rare & Neuromuscular Diseases Biobank, and in particular to Dr. Dan Cox, for the assistance in the storage and delivery of the patient samples used in this study. We also like to thank Dr. Rick Wansink and Ing. Walther van den Broek for helpful discussions and their work to isolate RNA. Furthermore, we would like to thank Dr. Pietro Spitali for the helpful discussions regarding the shared dysregulations observed with Duchenne muscular dystrophy.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Biomarker
KW - Lifestyle intervention
KW - Myotonic dystrophy type 1
KW - Peripheral blood
KW - RNA-seq
KW - Therapeutic Response
UR - http://www.scopus.com/inward/record.url?scp=85141519604&partnerID=8YFLogxK
U2 - 10.1186/s12916-022-02591-y
DO - 10.1186/s12916-022-02591-y
M3 - Article
C2 - 36352383
AN - SCOPUS:85141519604
SN - 1741-7015
VL - 20
JO - BMC Medicine
JF - BMC Medicine
IS - 1
M1 - 395
ER -