Brain Involvement iN Dystrophinopathies

Objective

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in childhood, with more than 25,000 patients in Europe. It is due to mutations in the DMD gene that preclude the production of the protein dystrophin. In addition to the progressive muscle weakness, 50% of affected individuals have debilitating central nervous system (CNS) co-morbidities, including intellectual disability, neurodevelopmental problems encompassing autism, Attention Deficit Hyperactivity Disorder and Obsessive Compulsive Disorder. These co-morbidities are due to the deficiency of multiple dystrophin isoforms in brain whose expression is differentially affected by the site of the DMD mutation. They represent a major obstacle for patients to live a fully independent life. Current therapies do not address these co-morbidities. The postnatal restoration of one dystrophin isoform using genetic therapies in the DMD mouse model improves the neurobehavioral phenotype. This raises the exciting possibility that some of the CNS co-morbidities could improve with genetic therapies in patients. We need to address several knowledge gaps before considering clinical applications of these therapies: i. dystrophin isoforms localisation in the CNS; ii. which of the neurobehavioural features of the dystrophic mice improve after dystrophin restoration, and circuitries involved; iii. deep phenotype patients to define robust outcome measures. This project developed in partnership with advocacy groups, meets gender criteria and offers for the first time insight into how dystrophins’ affect CNS function, and on the reversibility of the DMD CNS co-morbidities, providing essential information to the field of neurodevelopmental disorders, and for other syndromes arising from dystrophin associated proteins. Our efforts to develop novel therapies that can cross the blood brain barrier could be transformative for the field of neurodegeneration and neurodevelopmental disorders.

Field of science

/medical and health sciences/basic medicine/neurology/muscular dystrophy/duchenne muscular dystrophy
/natural sciences/biological sciences/biochemistry/biomolecules/proteins
/natural sciences/biological sciences/genetics and heredity/mutation
/medical and health sciences/clinical medicine/psychiatry/obsessive-compulsive disorder
/natural sciences/biological sciences/neurobiology

Funding Scheme

RIA - Research and Innovation action

Coordinator

UNIVERSITY COLLEGE LONDON

Address

Gower Street
WC1E 6BT London
United Kingdom

Activity type

Higher or Secondary Education Establishments

EU contribution

€ 1 733 428

Objective

Field of science

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Funding Scheme

Coordinator

Participants (18)

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