Assessing high affinity anti-latent TGFbeta binding protein-4 antibodies in combination with steroid treatment for DMD

Muscle is fragile in Duchenne Muscular Dystrophy (DMD) and the fragility causes incessant muscle breakdown. Beginning early in life, muscle breakdown in DMD causes the muscles to weaken. The heart and breathing muscles are also weakened in DMD, and the only available therapies are steroids, and for a small percentage of patients, exon skipping, which has a modest effect. New therapies are needed. We used mice to identify genes that can modify the outcome of muscular dystrophy, and we identified latent TGF-beta Binding Protein 4 (LTBP4) as a modifier of muscular dystrophy. We found genetic differences in human LTBP4 and showed that these genetic differences associated with longer walking duration, indicating that LTBP4 can be protective in DMD boys. In DMD boys, those with the protecting LTBP4 gene (about 12% of the total DMD population) walked longer especially when they were also given steroids. We now developed antibodies that block a key activity of LTBP4 protein, and we propose to test these antibodies in muscular dystrophy mice in order to develop data to justify a clinical trial in human DMD. Preliminary testing using short term treatments of this antibody in muscular dystrophy mice are encouraging, but more data is needed. We now worked with Solid Biosciences to develop new anti-LTBP4 antibodies with much higher potency, and we will test these antibodies in an animal model of muscular dystrophy in order to determine their safety and usefulness. We will also test these antibodies with and without steroids since we expect that steroids will promote their effectiveness. We found that giving steroids less often was less harmful to mouse models of muscular dystrophy, so we will test this steroid dosing scheme alongside anti-LTBP4 antibodies. We will also carry out serum profiling of the treated animals to identify biomarkers that can be used in humans to help accelerate a clinical trial in DMD.