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The Children's National Research Institute


We have several funded projects which focus on steroid signaling and gene expression in Duchenne muscular dystrophy (DMD) and other chronic inflammatory diseases. These are described briefly below. Techniques we use to address these questions include cell culture, molecular biology, gene expression analyses, ChIP-seq, gene knock-out (CRISPR cells and in vivo Cre systems), preclinical trials, live imaging, histology, serum analyses, proteomics,and expression profiling.

Can we more selectively "talk" to the GR to improve muscular dystrophy treatment?

Steroid side effects are one of the most prominent problems for DMD patients and families. These are a byproduct of chronic treatment with prednisone, the current DMD standard of care. The primary drug target of prednisone is the glucocorticoid receptor (Nr3c1, or GR). We find that the GR behaves differently when it binds to different ligands, and that GR efficacy and side effect pathways can be separated at the molecular level. This has led to the identification of vamorolone as a drug that can provide the efficacy of prednisone while eliminating its harsh side effects. Vamorolone is now in clinical trials for DMD. Currently, we are dissecting the molecular events that differentiate GR responses to different drugs, and also dissecting how the GR drives gene expression in DMD muscle and heart.

Can new MR antagonist & membrane stabilizing drugs improve heart health?

MRWe recently found that vamorolone has a new, additional property where it acts as an antagonist of the mineralocorticoid receptor (Nr3c2, or MR). This is analogous to eplerenone, a clinical MR antagonist recently found to improve heart strain in DMD patients.  In contrast, prednisone both acts as an agonist of the MR and worsens heart pathology in the mdx mouse model of DMD. Now, we are dissecting the roles of the MR vs. GR in dystrophic heart failure with the goal of identifying treatment approaches that improve heart health in DMD patients.

Previously, we found that vamorolone integrates into cell membranes in a manner analogous to cholesterol, and that this can improve the resistance or repair of cellular injuries. This is analogous to Poloxamer 188, a copolymer drug which is found to improve heart function in DMD model mice and dogs.

Moving forward, we are studying these two drug properties to see if vamorolone or other analogous drugs can provide a means to improve dystrophic heart failure. Since heart failure is a leading cause of death for DMD patients, this is a very important area of study.

Can we develop mechanism-defined biomarkers for inflammatory diseases?

There is a great need for non-invasive, objective,and statistically well-powered biomarkers that can measure drug responses in patients. This is particularly true for clinical trials in pediatric and rare diseases, where patients are particularly sensitive and clinical trial sizes are small. To address this need we are developing pharmacodynamic biomarkers that reflect anti-inflammatory efficacy, as well as safety biomarkers which can detect steroid side effects. By comparing serum from inflammatory bowel disease patients treated with prednisone and Remicade, we have identified a panel of molecular markers that respond to treatment with anti-inflammatory drugs. By analyzing serum from model mice, we are identifying target-specific responses to drug treatments. Moving forward, we will further develop these mechanism-defined markers with the goals of using them to improve clinical management and of using them as surrogate endpoints to improve clinical trials for new drugs.