Development of Non-Hormonal Steroids for the Treatment of Duchenne Muscular Dystrophy.

摘要

Glucocorticoids are standard of care for Duchenne muscular dystrophy (DMD) patients. The rationale to use glucocorticoids in DMD patients is largely empirical and the molecular mechanisms that help to improve muscle strength in DMD patients are unknown. Despite the success of glucocorticoids in increasing strength, their prescription in DMD remains controversial partly due to significant side effects associated with chronic glucocorticoid use in these patients. It has been proposed that side effects (e.g. metabolic) of glucocorticoids are due to transcriptional activation while beneficial effects (e.g. antiinflammatory) are due to transrepression indicating that designing selective glucocorticoid receptor (GR) ligands may maintain beneficial effects while reducing metabolic side effects (Coghlan et al., 2003). In collaboration with Validus Biopharma, we have developed glucocorticoid analogues (referred as VBP compounds) that retain the beneficial effects but not the side effects. We have previously shown that these compounds are potent NF B inhibitors and chronic in vivo administration of these compounds improves skeletal muscle function and histology in the mdx mouse model of DMD, yet reduce side effects commonly associated with existing glucocorticoids. After extensive screening and testing we have identified a lead candidate, VBP15, and preliminary data presented here characterizes the promising ADME and initial safety studies performed to date. Objective/Hypothesis: The objective of this proposal is to characterize the in vitro safety of VBP15 in human hepatocytes, and in vivo non- GLP acute toxicity and GLP 28-day repeated dose toxicity of VBP15 in rat and dog. This data will be used for an investigational new drug (IND) application to the FDA for use of VBP15 in muscular dystrophy. Specific Aims: In this proposal we will perform pre-IND in vitro safety (CYP induction assays in human hepatocytes) and in vivo toxicity studies.