BIND - Brain Involvement iN Dystrophinopathies

Abstract

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.

 

Notizie (in italiano)

 

Project details

Scientific responsability: Rita Selvatici

Funding source: HORIZON 2020 

Call: H2020-SC1-2019-Two-Stage-RTD

Start date: 01/01/2020 - end date: 31/12/2023

EU contribution: 6.666.325 €

EU contribution to UniFe: 60.000 €

Participants

  • University College London, United Kingdom
  • Consorzio Futuro in Ricerca, Italy
  • Academisch Ziekenhuis Leiden, Netherlands
  • Region Hovedstaden, Denmark
  • University of Newcastle Upon Tyne, United Kingdom
  • National Center of Neurology and Psychiatry, Japan
  • Centre National de la Recherche Scientifique CNRS, France
  • Universite de Versailles Saintquentin-En-Yvelines, France
  • Stichting Kempenhaeghe, Netherlands
  • Universita Cattolica del Sacro Cuore, Italy
  • Universidad Complutense de Madrid, Spain
  • Imagine Institut des Maladies Genetiques Necker Enfants Malades Fondation, France
  • Transpharmation Ireland Ltd, Ireland
  • Great Ormond Street Hospital for Children NHS Foundation Trust, United Kingdom
  • Stichting United Parent Projects Muscular Dystrophy, Netherlands
  • Synthena Ag, Switzerland
  • Pepgen Limited, United Kingdom
  • Stichting Duchenne Data Foundation, Netherlands
  • The Provost, Fellows, Foundation Scholars & the Other Members of Board of the College of the Holy & Undivided Trinity of Queen Elizabeth Near Dublin, Ireland