Optimizing membrane repair for the treatment of Duchenne muscular dystrophy

PROJECT ABSTRACT The long term goal of this project is to optimize a protein therapeutic for Duchenne muscular dystrophyDMDand potentially other muscle diseasesthat will enhance the repair capacity of muscle cell membranes that are compromised by mutations in the dystrophin dystroglycan complexMutations in the dystrophin dystroglycan complex result in Duchenne muscular dystrophyMyos Incis developing a novel recombinant construct of the tripartite proteinmitsuguminTRIMMGan essential regulator of membrane repair in skeletal and cardiac musclerhMGtherapy ameliorates disease pathology in the dystrophin null mouse modelstrongly suggesting that it may enhance repair and restoration of muscle function in DMDHoweverits large size and short serum half life make rhMGunsuitable for protein therapyThereforethe objective of this Phase I STTR project is to engineer the rhMGproteinthe result of which will be called MyoTRIMfor use in treating DMD by optimizing its functional and pharmacokineticPKpropertiesThis STTR project is a collaboration with Noah WeislederPh DOhio State Universitywho is the PIAimis to engineer a compact rhMGprotein containing key moieties that are required for membrane repairDeletion analysis and protein engineering approaches will be used to selectively delete regions that are not predicted to affect protein foldingThis will reduce protein size from the currentkDa to andltkDa while retaining the essential functional domains andD structureAimis to improve the PK characteristics of the engineered rhMGprotein by PEGylationA panel of three candidate rhMGconstruct resultant from Aimwill be modified by covalent and or non covalent attachment of polyethylene glycolPEGin order to extend its serum half life from the currenthr to andgthrProtein function will be tested in an ex vivo membrane repair assay and in the DBDBAcongenicDmdmdxDmdxmouse model of DMDOutcome measures will include serum half lifeprotein concentrations in serum and target tissuesand serum biomarkers for skeletal and cardiac muscle membrane integrityThis noveltruncatedfunctional PEGylated rhMGconstruct has great potential to improve muscle membrane repair to treat fatal muscular dystrophies and other forms of muscle diseaseindependent of gene or mutation classBy enabling membrane resealing and preservation of skeletal and cardiac muscle functionit would provide a complementary treatment approach to other therapeutic efforts now in developmentIt also may provide a platform technology to target other diseases involving compromised membrane integrity or necrotic cell deathsuch as cardiovascular disease and neurodegenerative disordersSuccessful completion of this Phase I STTR project will result in a novel rhMGPEG that is suitable for therapeutic development PROJECT NARRATIVE This Phase I STTR project is the first step in advancing a therapeutic that benefits the thousands of boys and young men suffering from Duchenne muscular dystrophyDMDa rare and fatal disease that is characterized by progressive muscle wastingMyosIncwill optimize a protein therapeutic to improve muscle cell stability and increase life expectancy for persons with DMDcompared to the current standard of careThis therapeutic would have a significant return in that it would allow this group of patients to lead more productive lives