Parent Project Muscular Dystrophy (PPMD) will provide $100,000 to Dr. Stanley Nelson of the University of California, Los Angeles, to examine the genomes of 40 boys with Duchenne muscular dystrophy who are either very mildly affected or very severely affected. The goal is to identify changes in genes other than dystrophin that may affect the course of the disease.
"We know that even boys who have exactly the same mutation in the dystrophin gene can have different disease courses," said Dr. Nelson. "It is very likely that other mutations or DNA variants in different genes may play a role in addition to dystrophin."
Dr. Nelson will use a relatively new technique known as "exome sequencing" to look only at the parts of the genetic code that spell out the recipe for proteins, known individually as "exons." Because the exons of the genome make up less than 1% of the total genetic material, this method provides a far more practical way to look at the coding regions (genes) for the some 20,000 human proteins without having to sequence the participants' entire genome.
For this project, Dr. Nelson will obtain blood samples primarily from boys and men participating in registries and other studies who have out-of-frame deletions or know they have Duchenne from a muscle biopsy data and have been identified as "outliers" for the speed at which the disease is progressing in the skeletal muscles—that is, they have very mild disease or very severe disease based on the age that the ability to walk was lost. The work will be conducted within the Center for Duchenne Muscular Dystrophy at UCLA with additional analyses supported by the Genomics and Bioinformatics Core of the NIAMS-funded UCLA Muscular Dystrophy Core Center.
Information generated from this project may serve a number of important functions, including providing critical insight into biological functions that affect Duchenne progression; allowing clinical trial sponsors to select participants with more similar disease courses based on genetic data (to design smaller, faster, and more powerful trials); and identifying new targets for drug development. It is also likely that some of the changes identified will be relevant to other forms of muscular dystrophy and muscle disease.
"The need to identify genetic modifiers is part of our strategic plan for research," said Sharon Hesterlee, PPMD's vice president for research. "We know this information may greatly speed the conduct of clinical trials by reducing the variability among participants in relation to other benefits. We are pleased to be able to fund Dr. Nelson's work."