In the first major finding from the UT Southwestern Wellstone Center, researchers were able to successfully stop the progression of Duchenne muscular dystrophy (DMD) in young mice. The team of scientists employed a gene-editing technique which, if safely scaled up for DMD patients, could lead to one of the first effective genome editing-based treatments for the lethal disease.
“The recent groundbreaking discoveries from the Olson laboratory using genome editing to correct the genetic mutation that causes DMD have accelerated the race to find a cure for this deadly disease,” expressed Dr. Pradeep Mammen, Associate Professor of Internal Medicine and Co-Director of the UTSW Wellstone Center. “The challenge now lies before Wellstone Center researchers to translate these discoveries in the mouse model of DMD into a therapy for patients with DMD.”
DMD is the most common and harmful form of muscular dystrophy among boys, affecting one in 3,500 to 5,000 young men, according to the Centers for Disease Control and Prevention. The disease progressively deteriorates muscle mass, causing weakness in the patient and often leading to premature death by his early 30’s.
Muscle fibers break down and become replaced with fibrous or fatty tissue, caused by mutatons in the X-linked DMD gene that encodes the protein dystrophin. The disease has been studied for nearly 30 years, yet no effective treatment currently exists, EurekaAlert reports. Patients with the disease typically end up developing heart muscle disease, or cardiomyopathy.
In the study published Thursday in Science, the team of scientists used a relatively new gene-editing technique known as CRISPR, or Cas9-mediated genome editing, to permanently fix the mutation that causes the disease in young mice.
“This is different from other therapeutic approaches, because it eliminates the cause of the disease,” said senior author Dr. Eric Olson, Chairman of Molecular Biology, and Co-Director of the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center at UT Southwestern.
Dr. Olson first used the CRISPR technique in 2014 to correct the mutation and prevent muscular dystrophy through the reproductive cells (or “germ line”) of mice. While this opened the door for genome editing-based therapeutics in DMD research, it also highlighted a string of challenges for clinical applications of gene editing, since germ line editing is not feasible in humans. Instead, researchers concluded that the technique would need to be revised to work with postnatal tissues.
With the new goal in mind, researchers tested new approaches by delivering gene-editing components to the mice via adeno-associated virus 9 (AAV9). The DMD mice treated with this technique produced dystrophin protein and began to show improved structure and function of sketal muscle and heart.
“AAV9 can efficiently infect humans in a tissue-specific manner, but it does not cause human disease or toxicity. It’s a molecular missile for gene therapy,” said Dr. Leonela Amoasii, a postdoctoral researcher in the Olson lab and co-lead author of the study.
“The CRISPR/Cas9 system is an adaptive immune system of single-celled organisms against invading virus. Ironically, this system was hijacked, we packaged it into a nonpathogenic virus, and corrected a genetic mutation in an animal model,” added Dr. Long, Instructor of Molecular Biology and co-author of the study along with Dr. Amoasii.
Now, the team is working to use this gene-editing technique to cells of DMD patients and in larger preclinical animal models.
“This study represents a very important translational application of genome editing of DMD mutations in young mice. It’s a solid step toward a practical cure for DMD,” said Dr. Rhonda Bassel-Duby, Professor of Molecular Biology and Co-Principal Investigator with Dr. Olson at the Wellstone Center.
“Importantly, in principle, the same strategy can be applied to numerous types of mutations within the human DMD patients,” added Dr. Olson, who also serves as Director of the Hamon Center for Regenerative Science and Medicine and holds the Annie and Willie Nelson Professorship in Stem Cell Research, the Pogue Distinguished Chair in Research on Cardiac Birth Defects, and the Robert A. Welch Distinguished Chair in Science.