Periodic Reporting for period 1 - BIND (Brain Involvement iN Dystrophinopathies)
Período documentado: 2020-01-01 hasta 2021-06-30
Duchenne muscular dystrophy (DMD) is the most common and severe muscular dystrophy in childhood, due to mutations in the DMD gene which affect the production of an essential protein for muscle integrity, named dystrophin. Unusually, the DMD gene also produced multiple other isoforms in the brain, and it is now well established that their deficiency in boys with DMD determines debilitating brain involvement which includes intellectual disability and neurodevelopmental problems such as Autism and Attention Deficit Hyperactivity Disorder.
• Problem to be addressed.
The ambition of the BIND consortium is to improve our understanding on the precise relationship between the DMD gene and the DMD brain involvement. This is important both for the DMD patient population, and for the wide society.
• Importance for society.
A deeper understanding of these difficulties will lead to better and globally adopted DMD standards of care guidelines and give rise to more timely and targeted monitoring and support strategies for these patients. Translational research work of our project will also have important broader implications for the neuroscience community. Firstly, DMD provides us with the unique opportunity to assess the direct correlation between the deficiency of dystrophin in brain and intellectual disability and autism or attention deficit disorder, and provide better understanding on how the brain works. Moreover, our genetic therapy studies will provide the unique opportunity to assess the degree of reversibility of these brain comorbidities in relevant dystrophic animal models, and facilitate the development of brain targeted therapies for other neurological disorders.
• Overall objectives.
In the human, we will provide the more comprehensive assessment of the frequency and severity of brain involvement in the largest group of DMD and other dystrophinopathy patients ever studied.
In our human and mouse pathology studies, we will characterise the structure of the protein complexes involved in dystrophin brain function.
in our dystrophic animal studies, we will assess the extent of improvement of brain features by genetic therapies aimed at restoring the production of the missing dystrophin proteins, paving the way to future clinical studies in the human.
• Problem to be addressed.
The ambition of the BIND consortium is to improve our understanding on the precise relationship between the DMD gene and the DMD brain involvement. This is important both for the DMD patient population, and for the wide society.
• Importance for society.
A deeper understanding of these difficulties will lead to better and globally adopted DMD standards of care guidelines and give rise to more timely and targeted monitoring and support strategies for these patients. Translational research work of our project will also have important broader implications for the neuroscience community. Firstly, DMD provides us with the unique opportunity to assess the direct correlation between the deficiency of dystrophin in brain and intellectual disability and autism or attention deficit disorder, and provide better understanding on how the brain works. Moreover, our genetic therapy studies will provide the unique opportunity to assess the degree of reversibility of these brain comorbidities in relevant dystrophic animal models, and facilitate the development of brain targeted therapies for other neurological disorders.
• Overall objectives.
In the human, we will provide the more comprehensive assessment of the frequency and severity of brain involvement in the largest group of DMD and other dystrophinopathy patients ever studied.
In our human and mouse pathology studies, we will characterise the structure of the protein complexes involved in dystrophin brain function.
in our dystrophic animal studies, we will assess the extent of improvement of brain features by genetic therapies aimed at restoring the production of the missing dystrophin proteins, paving the way to future clinical studies in the human.
• Pathology studies.
We have optimised techniques between the various laboratories to detect and quantify precisely dystrophin protein and RNA in human and mouse brains, with particular attention to assess the areas of the brain important for its function. We obtained ethical approval for acquiring human tissue from a wide range of international tissue banks, and we have shared the same mouse strains to ensure consistency between the different labs.
• Mouse behavioural studies.
We are assessing a wide range of behaviours in 3 different dystrophic mouse models which recapitulate different scenarios encountered with DMD patients. We have also started to assess the efficacy of different genetic techniques in increasing dystrophin production in these mice, and quantify the amount of protein restored, and the functional consequences in previously well established outcomes. This work is ongoing.
• Clinical studies
In the human, the Covid-19 crisis led us to introduce a modification of the original plan to assess all patients in hospital, with the introduction of a first step in which patients will be assessed with a novel on-line assessment tool which will allow us to reach out to a much larger patient population than originally considered. This part obtained ethical approval in 2021 and started recently. During the second reporting period we will also perform the in-hospital assessment of patients, and this protocol is now under ethical review. We already submitted the first few papers for peer review and have presented our findings at several national and international meetings. We have also refined our strategy for the internal and external data sharing of data obtained in the BIND consortium, with plans for these data to be made available to the community also after the end of the BIND project.
We have optimised techniques between the various laboratories to detect and quantify precisely dystrophin protein and RNA in human and mouse brains, with particular attention to assess the areas of the brain important for its function. We obtained ethical approval for acquiring human tissue from a wide range of international tissue banks, and we have shared the same mouse strains to ensure consistency between the different labs.
• Mouse behavioural studies.
We are assessing a wide range of behaviours in 3 different dystrophic mouse models which recapitulate different scenarios encountered with DMD patients. We have also started to assess the efficacy of different genetic techniques in increasing dystrophin production in these mice, and quantify the amount of protein restored, and the functional consequences in previously well established outcomes. This work is ongoing.
• Clinical studies
In the human, the Covid-19 crisis led us to introduce a modification of the original plan to assess all patients in hospital, with the introduction of a first step in which patients will be assessed with a novel on-line assessment tool which will allow us to reach out to a much larger patient population than originally considered. This part obtained ethical approval in 2021 and started recently. During the second reporting period we will also perform the in-hospital assessment of patients, and this protocol is now under ethical review. We already submitted the first few papers for peer review and have presented our findings at several national and international meetings. We have also refined our strategy for the internal and external data sharing of data obtained in the BIND consortium, with plans for these data to be made available to the community also after the end of the BIND project.
By studying the expression of the various isoforms of dystrophin in the mouse and human brain in greater detail than before, we have already identified novel localisation of some of its isoforms in brain structures important for its function. We have performed for the first time the characterisation of the severity of the brain involvement in a new mouse model which recapitulated the scenario found in many DMD boys with more severe brain involvement than average, and confirmed that this mouse (mdx52) has more severe brain involvement. We were also able to demonstrate for the first time that restoring brain dystrophins in this model by using genetic techniques leads to improvement which bodes well for future human studies.
In our clinical studies, we have found an unexpected but strong influence of the role of the dystrophin isoforms expressed in the brain also on motor function. We hypothesise this is related to defects in the processing aspects of these children, and this opens new concepts in the role between brain and muscle function, also relevant for the ongoing neuromuscular clinical trials planning and interpretation.
In our clinical studies, we have found an unexpected but strong influence of the role of the dystrophin isoforms expressed in the brain also on motor function. We hypothesise this is related to defects in the processing aspects of these children, and this opens new concepts in the role between brain and muscle function, also relevant for the ongoing neuromuscular clinical trials planning and interpretation.