Can Dystrophin-Replacement Therapies Improve Cognitive Function in DMD? Development of Strategies to Maximize Effectiveness and Avoid Detrimental Effects
Abstract
Scientific Objective and Rationale: DMD patients lose the expression of the dystrophin protein in muscle, leading to muscular dystrophy. However approximately one-third of DMD patients also have intellectual disability, with larger percentages experiencing cognitive and neurodevelopmental impairments such as learning and attention disabilities or neuropsychiatric disorders, suggesting that dystrophin plays important roles in regulating brain development and function. As DMD therapies with the potential for improving lifespan and overall health move into the clinical pipeline, it will be important to understand whether dystrophin restoration therapies could also be harnessed to improve cognitive and neuropsychiatric aspects of DMD. Currently, virtually nothing is known regarding dystrophin function in the brain, but the current proposal provides compelling preliminary evidence that a postnatal process termed “myelination” may be altered in DMD patients. Because myelination occurs postnatally and continues throughout childhood and the teen years, this suggests that dystrophin replacement may have a significant “window of opportunity” to help improve brain function. Determining whether that window exists, and what its parameters are for success or failure, is the objective of this proposal. In brief, we will take away dystrophin at particular times to determine when the brain needs it the most, as well as restore dystrophin at various times in dystrophin-deficient mice to determine whether replacement therapies have the potential to work, and if so, when is the ideal time to provide them. Lastly, we will determine if dystrophin replacement therapies have the potential to negatively impact postnatal brain development, as a subset of dystrophin proteins that are not expressed in muscle, but are found in the brain, are frequently still present and functional in DMD patients. Applicability of the Research: This research has the potential to help all DMD patients. First and foremost it will provide a proof-of-principle in mouse models of DMD as to whether dystrophin replacement therapies can be used to improve brain function for DMD patients, and if so, whether they should be used “as is” or should be modified. This is an important point because the molecular design of dystrophin replacement therapies have been guided by the ability of such therapies to mimic dystrophin function in muscle, but not in other tissues such as the brain, in which dystrophin has a some shared features but also some features that are distinct. Second, this study will tell us the best time frame for brain therapies in order to maximize chances for success. Third, the information gleaned from this study will also tell us whether dystrophin replacement therapies could have the potential to negatively impact brain function. This information will be especially useful in determining the risk of such replacement therapies to both DMD patients who lack appropriate dystrophin function in the brain, and also to DMD patients who have normal neurocognitive function, as some therapies may not be selective for muscle. Because this is a pre-clinical study, it will benefit future clinical designs and poses no current risk to patients. However, because a variety of dystrophin replacement therapies are already in phase 2 and phase 3 clinical trials for muscle, the knowledge gleaned by these pre-clinical studies should be able to be rapidly applied to future clinical trials with the same therapies that may need only to be slightly modified in order to permit brain expression. Excitingly, dystrophin-replacement therapies for DMD are showing promise, yet virtually nothing is known regarding how these strategies may impact the brain. If a diagnosis of DMD is identified early, which may be increasingly likely with early screening being advocated for, it will provide a clear window for therapeutic intervention for neurodevelopmental abnormalities. This will especially be
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110562
Entities
People
- Holly Colognato
Organizations
- Stony Brook University
- United States Army