Work Package 1: Project Management and Coordination
WP1 will address coordination and management of the entire project and be led by the coordinating institution, UCL, as one of the key stakeholders in the field of DMD clinical and basic research and has led on a previous EU grant EU grant (SKIP-NMD) on DMD. UCL‘s European Research & Innovation Office will provide dedicated central support and coordination to BIND, taking charge of the scientific, contractual and financial management and communication of the project.
Work Package 2: Localisation and interactome analysis of dystrophin isoforms in the mouse and human brain
WP2 will perform a comprehensive map of the human and mouse brain regions where various dystrophin isoforms are expressed, both during development and in the adult. In addition, we will characterise which proteins these isoforms interact with. Protein and RNA studies will be performed on human biobanked and on mouse samples. In the mouse models with inactivation of the different dystrophin isoforms, we will also assess the impact their deficiency has on interacting proteins.
Work Package 3: Behavioural and neuropsychological phenotyping of dystrophic mouse models lacking different brain isoforms
The BIND project will deep phenotype unique DMD mouse models that carry different dystrophin mutations with different consequences for the expression of various dystrophin isoforms in the brain. A range of cognitive and behavioural testing techniques will be used.
Work Package 4: Impact of brain dystrophins restoration on dystrophic mice phenotype.
The BIND project will assess the impact that postnatal restoration of dystrophin expression has on neuropsychological / behavioural features in the different mouse models using antisense oligonucleotides (AONs) exon skipping technologies, with naked or vectorized (AAV-U7 system) AONs. We will restore expression of Dp427; Dp427 and Dp140; and Dp71 brain dystrophin expression.
Work Package 5: Deep functional phenotyping of Duchenne muscular dystrophy and Becker muscular dystrophy patients
We will assess a large cohort of patients DMD and BMD from 7 European countries (. These patients will be selected based on their genomic deletions and the expected outcome of their mutations for brain dystrophins production. Neurocognitive and neuropsychiatric comorbidities will be assessed.
Work Package 6: Structural integrity in the DMD and BMD brain and in dystrophic mdx mice.
We will study the extent of CNS involvement in patients with DMD and BMD using state-of-the-art volumetric and tractographic analysis, functional MRI and spectroscopy. Patients will be selected on the basis of their mutations.
Work Package 7: Data Integration
This WP will study the data relationships across the murine and human data sets collected across WP2-6 to identify species-specific associations, followed by across species correlations relevant for the function of the different dystrophin isoforms. Interactome data will be assessed to identify a set of features that can be specifically associated with the different isoforms.
Work Package 8: Dissemination, Knowledge Management and Exploitation
Project dissemination will be led by DMD non-profit patient organisation partner World Duchenne Organization (UPPMD), assisted by partner Duchenne Data Foundation (DFF) and the many charities affiliated to WDO. They will liaise with other DMD charities across Europe to provide effective communication of goals, progress and results, to publicise our work as expeditiously as possible. They will also be in charge of producing the Data Management plan expanding partner’s DDF existing Duchenne Data storage platform UCL’s Division of Research and Innovation office at the GOSH Biomedical Centre will provide an Exploitation Manager to lead on knowledge transfer. UPPMD, DDF and UCL will set up the Dissemination and Exploitation Board and deliver the updated dissemination and exploitation plan.