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Developmental biology - Gene Therapy|
Slowing Duchenne Muscular Dystrophy In Dogs
"Children with DMD often die either because their heart loses the strength to pump, or their diaphragm becomes too weak to breathe. This encouraging level of dystrophin expression would hopefully prevent that from happening."
DMD affects one in 5,000 boys, leading to muscle and heart failure and premature death by their early 30s. Patients are forced into wheelchairs as their muscles degenerate and eventually onto respirators as their diaphragms weaken. No effective treatment exists, despite scientists knowing for decades a defect in the dystrophin gene causes the condition.
The work establishes proof-of-concept for single-cut gene editing in dystrophic muscle representing a major step towards a clinical trial. Next, the team will conduct longer studies to measure whether dystrophin levels remain stable and ensure these edits don't have adverse side effects.
Already Dr. Olson's team has corrected DMD mutations in both mice and human cells, making single cuts at strategic points on mutated DNA. The latest research applied this same technique in four dogs sharing the mutation most commonly found in human DMD patients. Scientists used the harmless adeno-associated virus (AAV) to deliver CRISPR gene-editing parts to exon 51, one of 79 exons making up the dystrophin gene.
CRISPR edited the exon, and within several weeks the missing protein was restored in muscle tissue throughout the body, including 92 percent correction in the heart and 58 percent in the diaphragm, the main muscle needed for breathing.
"Our strategy is different from other therapeutic approaches for DMD - as it edits the mutation that causes the disease and restores normal expression of the repaired dystrophin. But, more needs to be done before it can be used clinically," explains Leonela Amoasii PhD, Assistant Instructor of Molecular Biology in Olson's lab, and lead author of the study.
Dr. Olson hopes the next step will be a human clinical trial. Such a trial would be among several UT Southwestern's gene therapy center plans to launch in the coming years addressing numerous deadly childhood diseases. In the meantime, Olson's recent work has spawned a biotechnology company, Exonics Therapeutics Inc., which is working to optimize and bring this technology into the clinic. Exonics intends to add their approach to additional DMD mutations and other neuromuscular diseases having licensed the technology from UT Southwestern.
CRISPR, the genome-editing tool, introduced a mutation in a dog gene that, in effect, overrode a mutation responsible for a disease that mimics Duchenne muscular dystrophy (DMD). As a result, muscle cells in the dogs began to produce the dystrophin protein in many tissues, including the diaphragm and the heart. Although a similar study worked in mice, this is the first time researchers have reported success in a large animal model with this strategy. Some 300,000 boys around the world suffer from the crippling disease, which leads to respiratory and heart failure at a young age. The new study, reported online in this week's issue of Science, only involved four dogs and only followed the animals for 2 months, so longer and more thorough experiments must take place before human trials begin. But given that the only marketed treatment for DMD has limited effect, there's great hope that this novel intervention will live up to its promise.
Authors: Jon Cohen.
About the study
Dr. Olson is Professor and Chair of Molecular Biology at UT Southwestern. He holds the Pogue Distinguished Chair in Research on Cardiac Birth Defects, the Robert A. Welch Distinguished Chair in Science, and the Annie and Willie Nelson Professorship in Stem Cell Research. He is also the scientific founder of Exonics Therapeutics, launched in February 2017 to advance and commercialize his research. Olson's team collaborated with the Royal Veterinary College. The RVC's dog colony program was supported by grants from the Wellcome Trust, Muscular Dystrophy UK, and Duchenne Ireland.
Disclosure statements: Dr. Eric Olson is a scientific co-founder of, and consultant for, Exonics Therapeutics, and has license and investment interests with the company. Dr. Leonela Amoasii is a consultant for Exonics Therapeutics and is listed as co-inventor, along with Dr. Olson, of the strategy presented in the study.
The study was supported, in part, by Exonics Therapeutics Inc. and grants from the National Institutes of Health, the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, and the Robert A. Welch Foundation.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 2.4 million outpatient visits a year.
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Scientists use CRISPR gene editing to stop destruction of dystrophin by DMD in dog heart muscle. Dystrophin in each image appears GREEN. LEFT image illustrates normal distribution of dystrophin in dog heart muscle; MIDDLE loss of dystrophin in a dog suffering with DMS; RIGHT heart muscle after CRISPR re-introduces dystrophin. Image Credit: UT Southwestern