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Medical and health sciences
- Medical genomics
- Medical proteomics
- Diagnostics
Myotonic dystrophy type 1 (DM1), the most common adult form of muscular dystrophy,
affects virtually all tissues; the noncurable condition carries significant morbidity and
mortality impacting patient and family quality of life and socio-economic status. The
OPTIMISTIC clinical trial has shown that Cognitive Behaviour Therapy (CBT), a patienttailored
intervention to increase activity and enable patients to deal with their disease,
imparts strong benefit on patients’activity and participation (Lancet Neurology, 2018). We
now propose a multi-omic approach to identify the molecular signatures of the response to
this clinical intervention, taking advantage of the thorough clinical characterization of the
enrolled patients and the comprehensive set of serum samples at baseline and two followup
time points. Our lead hypothesis is that pathways associated with the positive response
to CBT can be consolidated or reinforced by conventional drug therapies targeting the same
pathways. A network-based bioinformatics approach shall be used to identify drug targets in
the molecular signatures. We shall repurpose clinically approved drugs for these targets
and measure their impact on molecular profiles of patients’induced pluripotent stem
cells, differentiated to multiple DM1-relevant cell types (cortical neurons, motorneurons and
myofibers). The effect of the most promising drug candidates will be evaluated in the
DMSXL and HSA-LR mouse models, employing cognitive, behavioural and motor
readouts that are reminiscent of the clinical readouts in the OPTIMISTIC trial. The systemic
and muscle-restricted expression of the transgene in two different mouse models allows for
exploration of the brain/muscle axis in the cognitive and behavioural aspects of the
disease. Repurposed drugs can be evaluated in isolation or combination with other
interventions like CBT in future clinical trials for DM1 and other neurological conditions. The
drug repurposing strategy based on the reverse engineering of a positive response to
a behavioural intervention may set the scene for future drug development trajectories for
rare diseases.