Assessing High-Affinity Anti-Latent TGF-beta Binding Protein-4 Antibodies in Combination with Steroid Treatment for DMD
Abstract
Background and Goals: 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 are needed. We now work 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. Impact: These studies are designed to rigorously test to whether anti-LTBP4 antibodies are effective. If successful, these data will be used to justify a clinical trial of human anti-LTBP4 antibodies in DMD. While many different therapies are currently in development for DMD, often these treatments require DMD boys to have specific mutations in order to qualify for those treatments. Anti-LTBP4 antibodies can be used in all DMD individuals, and anti-LTBP4 antibodies are expected to be compatible with other therapies like exon skipping and viral gene therapy. Antibodies are now routinely used to treat diseases like rheumatoid arthritis and psoriasis with great effect. Antibodies are generally well tolerated and have proved beneficial for other chronic diseases. This work is being conducted at Northwestern University Feinberg School of Medicine in the Center for Genetic Medicine under the direction of Elizabeth McNally, Ward Professor and Director of the Center for Genetic Medicine. This work responds to multiple aspects of the Duchenne Muscular Dystrophy Research Program through the Congressionally Directed Medical Research Programs. Cardiac studies: LTBP4 is highly expressed in the heart and gene changes in LTBP4 correlate with heart involvement in DMD. Anti-LTBP4 antibodies are expected to improve cardiac function. Endocrinology: Steroid use has many side effects in DMD boys mediated by hormonal effects. We will test steroids in combination with anti-LTBP4 antibodies using a novel steroid dosing strategy that reduces side effects. Pulmonology: We will assess the effects of anti-LTBP4 antibodies with and without steroids on lung function in animal models of DMD. Therapeutic Development Path: This primary goal of this work is to provide information that supports a clinical trial of anti-LTBP4 antibodies in DMD. Biomarker Studies: As an exploratory goal, we will conduct serum profiling in order to develop biomarkers that can be applied in the human clinical trial
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810244
Entities
People
- Elizabeth Mcnally
Organizations
- Northwestern University
- United States Army