New Therapies for Fibrofatty Infiltration

Fibrofatty infiltration, the replacement of muscle tissue with hard fibrous tissue and fat, takes place early in Duchenne's muscular dystrophy and is thought to be one of the main causes of loss of muscle function. In addition, it interferes with cures that try to restore muscle function or prevent its continued loss. At the moment, no therapy is directed specifically to prevent fibrofatty infiltration, in part due to a poor understanding of what causes it and where it originates. Over the past several years, others and we have described a novel cell type present in muscle that responds to chronic damage by generating fibrous material and fat, which we called fibro/adipogenic progenitors. More recently, we have conducted a search for drugs that are capable of preventing these cells from giving rise to fibrofatty infiltrates and have identified promising candidates of three different classes. Here, our objective is to move the testing of these compounds from preclinical studies in vitro to testing in animal models of Duchenne's muscular dystrophy, a required step toward human testing. Thus, our goal is perfectly in line with the Fiscal Year 2015 Focus Area of 'extending preclinical data in support of the therapeutic development path.'

Our approach represents a new untested path toward the therapy of Duchenne's muscular dystrophy. While it does not address the cause of the disease and as such cannot cure it, by helping maintain muscle function longer it will preserve the quality of life of patients, for example, by preventing breathing problems, and make them more responsive to other therapies directed at restoring dystrophin expression. As our approach should prevent, rather than eliminate, fibrofatty infiltration, it is more likely to help patients at an early stage of disease, but as fibrofatty infiltration keeps progressing throughout the life of patients, it should be useful to all.

Importantly, the compounds that we have identified are easily applicable to human patients. Some of them are drugs already in clinical use (kinase inhibitors), some of them are already being extensively tested for other diseases (bromodomain inhibitors), and some of them are on a clear pathway to clinical testing (steroidal lactones). Depending on which of these compounds shows efficacy, testing in patients could take place as early as within 5 years.