Protein Supplementation Therapy to Increase Membrane Repair to Treat Duchenne Muscular Dystrophy
Abstract
Scientific Objective and Rationale for the Proposed Project: The overall goal of this DMDRP Translational Research Award proposal is to expand on our existing efforts to develop a novel protein therapeutic intervention for the treatment of Duchenne muscular dystrophy (DMD). This therapy increases the repair capacity of muscle cell membranes of skeletal and cardiac muscle to compensate for the membrane fragility produced by the mutations that cause DMD. This therapeutic protein is based on human protein, mitsugumin 53 (MG53) protein, which is only expressed in heart and skeletal muscle, where it acts as an essential regulator of membrane repair to protect muscle cells against damage. Our previous published studies show that isolated human MG53 (rhMG53) protein binds to places where the membrane of muscle is damaged and helps to form a patch, much like a patch on a tire, that enhances membrane repair in DMD patient cells and dystrophic mouse models. We now seek to develop an improved therapy to enhance repair and restore muscle function that is compromised in DMD. In this proposed project, we will show new data where we optimized the original rhMG53 to produce a new version of rhMG53 (that we now call MyoTRIM) to eliminate off-target effects of the original protein. We found MyoTRIM could increase membrane repair in myoblasts from DMD patients, illustrating the translational potential of this therapeutic approach. Thus, we propose in this DMDRP Translational Research Award proposal to expand on our existing preclinical translational data in support an appropriate therapeutic development path for MyoTRIM to treat DMD. This project will involve a team led by the researcher who developed the initial rhMG53 and the new MyoTRIM protein as well as an expert in development of treatments for DMD with deep ties to the DMD patient community. FY22 Translational Research Award Focus Areas Addressed by the Proposed Project: Our proposed project addresses multiple FY22 Translational Research Award Focus Areas. First, the use of MyoTRIM as a therapeutic for DMD would improve the function and quality of life and extending the lifespan of all individuals with DMD, as all patients would be eligible for use regardless of age or type of mutation. Second, this is a translational study that uses animal models to test a novel interventions targeting both the heart and skeletal muscles affected in DMD. Third, we will expand our existing preclinical translational data in support of a therapeutic development path. Thus, we address several of the focus areas for a Translational Research Award. Applicability of the Research to the DMD Patient Community: 1. What Types of Patients Will It Help and How Will It Help Them? Because MyoTRIM targets the muscle cell membrane repair process and does not depend on the type of mutation in the DMD gene, this therapeutic should be effective against all forms of DMD and potentially against other types of muscular dystrophy that result from unstable muscle membranes, like Becker and some of the Limb Girdle Muscular Dystrophies. Additionally, MyoTRIM function is affected by the presence of antibodies against AAV or the age of the DMD patient; thus, this approach can be effective in all individuals with DMD. Additionally, we know that MyoTRIM is effective in both heart and skeletal muscle; thus, MyoTRIM may be useful to treat both skeletal and cardiac muscle damage seen in DMD patients. 2. What Are the Potential Clinical Applications, Benefits, and Risks? MyoTRIM is a protein supplementation approach where this protein is injected to increase the levels of a protein that already appears in the body normally, much like insulin treats diabetic patients. Injecting MyoTRIM will increase the ability of heart and skeletal muscle to resist damage and allow muscle cells to survive when they would have otherwise died. The risks associated with the use of MyoTRIM are minimized because it is based on
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310940
Entities
People
- Noah Weisleder
Organizations
- Ohio State University
- United States Army