By Maggie Wahl – 03/19/2014
Dr. John Day from Stanford University, co-chairman of the conference, opened the final sessions today with a brief look back at the history of research in Duchenne muscular dystrophy, reminding the audience that from the mid-19th century to the mid-1980s, such research was mostly aimed at describing the disease and searching for its underlying cause, which turned out to be a genetically caused deficiency of the dystrophin protein in muscle cells.
To understand how this dystrophin deficiency occurs, as well as its consequences, it was necessary for scientists to master what is now called the “central dogma of biology,” the way DNA is transcribed into RNA and then into protein. To help the audience remember this fairly simple but elegant process, he showed a video from the Howard Hughes Medical Institute that anyone can access.
Since the 1980s, we’ve learned enough about the dystrophin gene and the protein that’s made from it to think about gene transfer therapy, which involves putting in new dystrophin genes; changing the way cells process the dystrophin gene, which involves strategies like exon skipping and read-through of premature stop codes; and using muscle stem cells as therapeutic agents.
We’ve also learned that there’s a protein that’s similar to dystrohin, though shorter, that comes from a completely different gene and that also can be exploited as a therapy for dystrophin deficiency. Known as utrophin, this protein is now the basis of an experimental therapy in which a small molecule is being used to increase utrophin production.
We also know more than ever about some of what Day called the “downstream” effects of dystrophin deficiency, such as inflammation in muscle cells, and mislocation of proteins that normally interact with dystrophin, such as one called nitric oxide synthase. These phenomena likewise are targets for development of new therapies, with new anti-inflammatory agents coming down the pipeline, and drugs called PDE5 inhibitors (tadalafil and sildenafil are in this class) that may help compensate for nitric oxide’s misplacement and improve blood flow to active muscle fibers.
The implications for MDA clinics, he said, are now clear, not only for Duchenne dystrophy patients but for those with other neuromuscular disorders as well. First, precise genetic diagnostic testing should be available for all neuromuscular disease patients. Second, standardized care needs to be provided for as many disorders as possible, so that clinical trials testing new treatments can be conducted without the statistical “noise” that results when patients in different centers receive different types of general care. And third, Day said, all patients being seen in MDA clinics should have the opportunity to participate in a clinical trial.
Day, still vigorous but with graying hair and the wisdom of middle age, said he remembers the day Lou Kunkel of Harvard first came to the University of California, San Francisco, to talk about the identification of the dystrophin gene. It was the late 1980s, and Day was still in his residency training at UCSF. “That day cemented my commitment to neuromuscular disease,” he said.
But it was just the beginning. The work of Kunkel and many others would later show not only the vital structural role of dystrophin but also its complex role in signaling pathways. “Understanding these molecular mechanisms was crucial to treating this disease,” he said, introducing the first of several talks that would describe clinical trials that could scarcely have been imagined just 30 years ago.