Impact of Dystrophins Restoration on Neurobehavioral Deficits in Dystrophic Mouse Models – BRAIN-DYS

Antisense Oligonucleotides (ASO) and gene therapy approaches hold great promise for the treatment of genetic diseases and Duchenne muscular dystrophy (DMD) in particular. Some of these therapeutic strategies have even reached market approval, however none of the currently approved therapies addresses the brain comorbidities associated with DMD, which are found in more than 50% of affected individuals. These include intellectual disability, neurodevelopmental problems such as autism, Attention Deficit and Obsessive-Compulsive Disorder. In contrast to the muscle and cardiac phenotypes, little is known about the reversibility of these central deficits and only few therapeutic studies have focused on the brain aspect of DMD.
We have previously characterized and identified specific and pertinent neurobehavioral outcomes in mouse models of DMD as well as engineered and optimized all the genetic tools required for an efficient restoration of the brain dystrophin isoforms responsible for brain defects. Preliminary results indicate that some neurobehavioral deficits can be improved by partial rescue of Dp427 in the postnatal brain. These results set the ground for our proposed BRAIN-DYS project aiming to restore different dystrophin isoforms in order to improve cognitive / behavioral features in various DMD mouse models, representative of the most common mutation profiles observed in patients. In particular, we aim to rescue the main isoforms expressed in the brain using antisense and gene therapy approaches to assess the full reversibility of these deficits.
Our multidisciplinary consortium combines the complementary expertise in antisense/gene therapy and neurobiology of DMD to achieve the major milestones of this project. The BRAIN-DYS project has the potential to bring gene-correction strategies closer to a full compensation of symptoms and comorbidities in DMD patients.