Objectives and Approach
1. Project’s Goals
Our primary aim is to increase our knowledge on the functions of dystrophin isoforms in the CNS in order to reveal the causative mechanisms underlying brain co-morbidities in DMD and BMD. We will comprehensively describe the brain endophenotypes in the largest cohort of DMD and BMD patients to identify adequate and validated clinical screening tools, with recommendations for clinical management, that will be disseminated to the national and international clinical networks via the ERNs. We will determine which aspects of the abnormal dystrophic mouse behaviours can be reversed by postnatal dystrophin restoration. We also aim to identify robust outcome measures that will lay down the foundation for future treatments targeting the deficiency of dystrophin in the brain of DMD boys.
Our specific objectives are:
- Determine the high-resolution distribution and protein interactions of different dystrophin isoforms in mouse and human brain.
- Determine the correlation between loss of specific dystrophin isoforms and different brain co-morbidities in the mouse.
- Determine which brain co-morbidities can be restored post-natally.
- Characterise how loss of different dystrophin isoforms impacts brain co-morbidities in patients.
- Engage the DMD and BMD patients’ community.
- Exploitation of novel anti-sense oligonucleotides (AON) that could cross the blood-brain barrier to treat neurological conditions.
- To develop a brain comorbidity supercluster to enhance exploitation potential.
- Dissemination of project outcomes across Europe to patient advocacy groups and other stakeholders.
2.1 Expected Impacts
Our work will have significant impact in the following fields of medicine:
- Clinical aspects related to DMD and BMD muscular dystrophies and their brain comorbidities;
- Neurodevelopmental conditions with associated neurocognitive and neurobehavioural comorbidities;
- Translational research for conditions in which targeting the brain with genetic therapies is desirable;
The severe impact of the CNS co-morbidities in DMD and BMD, and the growing number of adults with DMD as a result of evolving standards of care and improved survival into adulthood of affected individuals, means that the societal impact of a successful intervention to improve our understanding on the neurocognitive and neurobehavioural features of DMD would apply to the lives of the > 10,000 patients with DMD with these complications who currently live in the EU, and 100,000-150,000 worldwide, and their families.
Assessment of the prevalence of the different brain comorbidities, their severity and their correlation with the different genotypes (hence different dystrophin isoforms) across several EU countries will influence the way every child with DMD is assessed and has the comorbidities acknowledged and recognised as early as possible. For some of these comorbidities, early recognition and intervention leads to improved outcomes (i.e. speech and language for speech delay; early recognition of learning difficulties and appropriate school support provision; referral to appropriate services for those patients in whom the severity of some of the comorbidities affects social functioning (for example ADHD; compulsive behaviours). A refined and validated assessment tool and robust information on the prevalence and severity of these comorbidities will provide us with ideal tools to engage national health care providers and the ERN for implementing changes in assessment and care that will have a durable impact. Increasing the strength of the evidence of the CNS co-morbidities in DMD and BMD, and linking this to the EU ERN, could allow the enforcement of the standards of care suggestions at the national level.
DMD/BMD provide a unique opportunity to link specific proteins to brain areas and circuitries and CNS co-morbidities. This has important implications for the deeper understanding of the DMD/BMD neuropsychiatric syndrome and the often-associated intellectual disability. Our work on DMD and BMD could further our understanding the brain involvement (or aspects of brain involvement) of other conditions with primary involvement of genes/proteins associated directly, or as part of more complex networks, with dystrophin and consequently help the understanding of the molecular pathology of other conditions.
The deep phenotyping of the dystrophic mouse models, and the insight on the cells and dystrophin-associated proteins involved in the phenotypes observed, will provide invaluable information regarding the dystrophin circuitries that could a deeper understanding of their molecular basis.
Beyond DMD, the postnatal reversibility of complex CNS endophenotypes would provide extremely valuable information to the research for example on ASD, and on how for example GABAergic and purinergic circuitries are involved in these co-morbidities. Aspects of abnormal social behaviour that characterise the mdx mouse are of broader interest to the field, and our deep phenotyping of the role that different isoforms have on these aspects and the possibility to improve outcome following postnatal dystrophin restoration, could be of great value both to establish models and know-how on the developmental aspect of some of these comorbidities, but also, importantly, on how much they could be reversed postnatally.
Our work will be the first in which different AON chemistries will be compared head-to-head for their efficiency and safety to target a gene in the brain after direct delivery. This will have impact for drugs already under development for muscular dystrophy and would provide an almost immediate possibility to consider their use for addressing the brain comorbidities in DMD. But if another AON chemistry demonstrates clear superiority, the implications not only for DMD brain therapies, but also for other conditions in which AON could be considered, would be of great importance. Novel AON chemistries capable of crossing the blood brain barrier opens the door to the possibility of considering systemic AON therapies to treat CNS disorders. A careful assessment of the pros and cons of locally delivered AON vs systemic delivered next generation AONs will be essential to take this field forward towards future translational research implications of these findings. The work done in BIND could therefore provide the 2 SME partners a strong competitive advantage for future interactions with larger industrial partners to take forward AON for brain disorders.
Academic investigators in the consortium are also interested in application of AON and of AAV in other neurodevelopmental disorders, and the information obtained from the mdx mouse work will provide a wealth of information that could be exploited for other brain conditions.
3. Expected Results
- Validated clinical assessment tool to be adopted in the EU clinics when addressing the CNS comorbidities in DMD and BMD.
- Optimal outcome measures for future interventional trials focused on improving brain outcomes for DMD and BMD.
- Identification of the optimal chemistry(ies) for targeting different parts of the brain.