Purpose and Objectives of the Program Project. 

The goal of the Program application is to conduct translational research focused on experimental therapeutics of Duchenne muscular dystrophy, with the goal of expediting translational approaches that could improve patient care and quality of life.  DMD is the most common childhood lethal genetic disorder.  The primary genetic lesion underlying Duchenne dystrophy is well understood.  Mutations of the Duchenne muscular dystrophy gene lead to complete, or nearly complete loss of the 427kDa dystrophin protein from the intracellular face of the plasma membrane (Hoffman et al. 1987; Hoffman et al. 1988).  What is less well understood is the downstream pathophysiology of the disease, and the only effective therapeutics to date is chronic administration of corticosteroids.  The mechanism of action of corticosteroids is also not understood. 

Patients show an onset around 4-5 yrs of age, with subsequent progressive clinical course, despite the biochemical defect being present from fetal life.  Corticosteroids slow the progression of the disease, and lead to a rapid increase in strength and muscle function.  Yet the mechanisms of the beneficial actions of steroids are poorly understood.  Indeed, corticosteroids are clearly catabolic to normal muscle, yet seem to have the opposite effect on DMD muscle.  Moreover, clinical studies and clinical trials have shown that the clinical variability between Duchenne muscular dystrophy patients is extensive, and this variability complicates the conduct of clinical trials.  The response to corticosteroids is also variable, with some patients appearing to be “responders” and some “non-responders”.

The pathophysiology downstream of dystrophin deficiency is almost certainly a highly complex process.  Myofiber membrane instability, changes in the myofiber microenvironment from unstable myofibers, myofiber necrosis, infiltrating inflammatory cells, connective tissue proliferation, vascular remodeling, regeneration via stem cells, and possible exhaustion of stem cells, all likely contribute to the presentation, progression, and drug responsiveness of Duchenne muscular dystrophy.  

Four distinct lines of experimental therapeutics are pursued in this Program: oligonucleotide splicing, stem cells, muscle bulk (reversal of atrophy), and high throughput drug screens.  These four projects, and the investigators responsible, were chosen through a systematic process including discussions between stake holders (parents), pharmaceutical representatives, biotech venture capitalists, and scientists.  The history of this application is very important to emphasize.  This is described in more detail in the following sections of text, however here we point out that these projects were chosen based upon the most promising approaches, and the best laboratories to pursue these approaches.  The four projects are:

• Project 1.  Developing antisense oligonucleotide-mediated therapy towards clinical trials for Duchenne muscular dystrophy.  Qi Lu PhD.  Carolinas Research Institute.
• Project 2.  Characterization of the highly myogenic minority population of muscle stem cells.  Terence Partridge, PhD.  Children’s National Medical Center
• Project 3.  Modulation of atrophy pathways in muscular dystrophy therapeutics. H. Lee Sweeney, PhD.  University of Pennsylvania.
• Project 4.  Development of assay systems for small molecule high throughput screens for muscular dystrophy.  Carrie Miceli, PhD.   University of California, Los Angeles.

Each of these components has extensive feedback with each other, and thus extensive synergism between projects.

The focus of the Program specifically on Duchenne muscular dystrophy enables a synergism of research approaches, expertise, and reagents.  The highly interdisciplinary approach including experts in muscle, molecular studies, and stem cell biology, ensures that the whole is greater than the sum of the individual parts.