P.204 Blood based biomarker discovery in DM1

Abstract

The to date largest clinical trial in myotonic dystrophy type 1 (DM1), OPTIMISTIC, has demonstrated significant positive effects of cognitive behavioural therapy (CBT) on the capacity for activity and social participation. Through a process of reverse engineering, the ReCognitION study aims to identify druggable biomarkers associated with the clinical improvement observed in the OPTIMISTIC cohort. Based on full blood samples collected during OPTIMISTIC, paired mRNA sequencing was done for 27 patients of the intervention group (before and after the intervention) and proteomic profiling (data independent acquisition, DIA) for a total of 451 samples (before and after the intervention, both control and intervention group). Linear mixed effect models were used to identify biomarkers associated with the disease causing CTG-expansion and the mean clinical improvement across all outcome measures. We identified 608 genes for which 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 significantly associated with both returned to more normal levels in patients who improved clinically. This 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 <i>DNAJB12, HDAC5</i> and <i>TRIM8</i>, each belonging to a protein-family that is being studied in the context of neurological disorders or muscular dystrophies. Preliminary analysis of the proteomics data revealed that 102 peptides and 48 proteins were associated with the CTG-repeat expansion. Taken together, these findings demonstrate that DM1 relevant disease signatures can be identified in peripheral blood on multiple biological levels, opening new avenues for drug discovery and therapy efficacy assessment.