Project

Recognition and Validation of Druggable Targets from the Response to Cognitive Behaviour Therapy in Myotonic Dystrophy type 1 patients from Integrated -Omics Networks

Code
3G0I2818
Duration
01 April 2019 → 31 March 2021
Funding
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Medical genomics
    • Medical proteomics
    • Diagnostics
 
Project description

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.