History leading to the Program Project.

Research on Duchenne muscular dystrophy and other types of muscular dystrophy are under-represented relative to other disorders.  Indeed, if one searches the NIH CRISP database for Huntingtons, Pediatric AIDS, Cystic Fibrosis, or Duchenne muscular dystrophy, and graphs the number of grants per year, one obtains the following graph:

As Duchenne muscular dystrophy is much more frequent than these other disorders, the graph becomes even more skewed when dividing by the number of patients.  Also, pediatric AIDS and Cystic Fibrosis are declining in incidence due to effective treatments and screening methods.  Duchenne dystrophy can not be screened effectively due to the high mutation rate, and there are no cures.  Duchenne dystrophy also has a particularly severe disease burden, in that patients require extensive care as their health gradually deteriorates.

The under-representation of Duchenne dystrophy research is likely due to a number of reasons.  DMD funding has been spread between three NIH institutes (NINDS, NIAMS, NICHD) with few programs directed at building research on DMD at any particular institute.  Also, NIH funding has been more focused on cause, rather than translational research.  While the DMD gene was the first human gene to be identified by positional cloning methods, translational research towards therapeutics has been relatively slow.  Indeed, very few clinical trials have been conducted in DMD since 1987, when the disease gene was first identified.

To begin to attempt to alleviate the under-representation of Duchenne research, and the paucity of translational research, efforts were undertaken to encourage the Department of Defense to fund translational research in DMD, and this Program Project is in response to initiatives by the Department of Defense. 

This current Program Project was designed through a systematic consensus-building approach, where the research areas holding the most promise for DMD therapeutics were identified through a series of meetings, and then the best laboratories to carry out this research were identified.  In September 2004, the Foundation to Eradicate Duchenne (FED) convened a 2 day meeting of about 70 scientists, pharmaceutical companies, biotech venture capitalists, and parents, with the express purpose of providing a survey of translational approaches in DMD, and then prioritizing those that are both most promising, and also were in most need of further funding.  This meeting was then followed up with another two smaller meetings in New York City, with key stake holders and scientists, to further refine the list of priorities, and then to identify the best laboratories to undertake the research in the key areas.

The four key areas were:

1.      High throughput drug screening (development of assays)

2.      Oligonucleotide-based alteration of dystrophin gene splicing

3.      Muscle stem cell biology

4.      Mouse model in vivo screening of potential therapeutic agents

To pursue the high throughput drug screening, we recruited Dr. M. Carrie Miceli, Stanley Nelson, and Linda Baum from the University of California Los Angeles.  Together, they provide the multidisciplinary expertise to develop an ambitious series of in vitro assays targeted as specific aspects of DMD cell biology and pathophysiology.  To pursue the oligonucleotide-based alteration of dystrophin gene splicing, we recruited Dr. Qi Lu, a recent hire by the Carolinas Medical Center, who, with Dr. Partridge, has published the most impressive in vivo delivery of oligonucleotides and subsequent dystrophin production in muscle to date.  For muscle stem cell biology, Dr. Terence Partridge was recruited from Hammersmith Hospital to Washington DC.  For in vivo drug screening, Dr. H Lee Sweeney is an authority on translational research in the dystrophies, and he will investigate anti-apoptotic methods to prevent muscle atrophy.  We also will establish a murine model core facility that can provide dystrophy models to both program investigators and other sites.