Scientific Results
The key findings from the scientific work packages are outlined below. For a more in-depth discussion, please refer to the published scientific articles.
Work Package 2: Localisation and interactome analysis of dystrophin isoforms in the mouse and human brain
WP2 has advanced our understanding of dystrophin in the mouse brain by identifying novel interactors and protein complexes associated with each of the dystrophin isoforms. Additionally, WP2 carried out a thorough and systematic analysis to map the distribution of each dystrophin isoform across various human and mouse brain regions. This provided crucial insights into how different isoforms are localised in distinct areas of the brain, revealing the potential roles they play in brain function and development. By connecting the isoform distribution patterns to their molecular interactions, WP2 has significantly enhanced our understanding of the complex dystrophin’s biological
Work Package 3: Behavioural and neuropsychological phenotyping of dystrophic mouse models lacking different brain isoforms
WP3 conducted an in-depth exploration of the phenotypic differences observed in mouse models lacking specific dystrophin proteins; Dp427, DP427 and Dp140, Dp71, and all dystrophins including DP71. Using a range of cognitive and behavioural testing techniques, this in-depth analysis revealed the distinct impacts of each dystrophin’s absence on brain function. By uncovering these differences, WP3 has made significant strides in understanding the underlying mechanisms of DMD neurobiology and highlighted important factors and markers to consider in developing more targeted treatments for patients with different forms of dystrophin deficiency.
Work Package 4: Impact of brain dystrophins restoration on dystrophic mice phenotype.
WP4 investigated the effects of restoring dystrophin expression on neuropsychological and behavioural traits in DMD mouse models. Using antisense oligonucleotide exon-skipping technology, researchers aimed to determine whether reinstating dystrophin expression could improve cognitive and behavioural outcomes. By assessing key neurological and psychological markers, WP4 provided valuable insights into the potential of exon-skipping therapies to address brain-related symptoms in DMD, paving the way for more comprehensive treatment approaches.
Work Package 5: Deep functional phenotyping of Duchenne muscular dystrophy and Becker muscular dystrophy patients
WP5 offers a comprehensive review and systematic assessment of the various brain related comorbidities (cognition, learning, behavioural and emotional) that may be present in individuals with DMD and BMD, highlighting how different mutations affect the distinct brain isoforms of dystrophin. Harmonisation of assessment over the different participating countries and centres was established. Data may result in a Duchenne toolkit to assess brain related comorbidities. The work package also focused on the development of a rapid screening tool, designed to help identify individuals at risk of brain related comorbidities. The consortium has agreed to make this valuable tool available in collaboration with World Duchenne Organisation (WDO) to the broader community, aiming to improve early detection and intervention for those affected by these conditions.
Work Package 6: Structural integrity in the DMD and BMD brain and in dystrophic mdx mice.
WP6 focused on analysing various brain characteristics, including total brain volume, cortical volume, white matter integrity, default mode network connectivity, and total brain perfusion in patients with DMD and BMD, as well as age-appropriate controls. WP6 findings in the DMD population align with existing research, while the data gathered from the BMD group is entirely novel. In preclinical MRI studies, WP6 are concentrating on identifying both structural and functional signatures that could be used to monitor responses to therapeutic interventions, offering potential tools for evaluating treatment efficacy in the future.
Work Package 7: Data Integration
The integration of data across the various work packages has allowed WP7 to identify specific cell types where dystrophin interacts with newly discovered binders, and to connect dystrophin expression to brain regions and behavioural outcomes in mice. Additionally, WP7 have modelled the structure of the data to ensure its long-term usability, enabling further integration, analysis, and future studies based on the work conducted in BIND. The WP7 data integration efforts have been crucial for: i) linking the different components of the BIND project; ii) expanding collaboration with other research teams; and iii) facilitating the “FAIRification” of the data, ensuring that it is findable, accessible, interoperable, and reusable to promote future collaborations at various levels.
Work Package 8: Dissemination, Knowledge Management and Exploitation
