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Experimental gene therapy cbadettes for Duchenne muscular dystrophy have been modified to provide better performance. The cbadettes, which carry the therapy into the muscle cells, contain new versions of a miniaturized processing gene. Microdystrophin, as the treatment is called, has been restructured to improve its functionality.
Revised versions have been developed and tested in UW Medicine laboratories on animal models of muscular dystrophy. The results are published in Molecular Therapy, a Cell Press newspaper.
Duchenne muscular dystrophy is a genetic disease that shortens life and is characterized by debilitating muscle weakness that worsens over time. The disease affects men almost exclusively. It is caused by mutations in the X chromosome that interfere with the production of dystrophins, which build and maintain healthy muscles.
Viral vectors are being explored as cargo ships for administering gene therapy to several types of diseases. For Duchenne muscular dystrophy, researchers design and test vectors that send the treatment directly into the muscle cells. Some of these vectors target mutations. Others embody a synthetic dystrophin gene.
The vehicles carrying treatments are re-tooled from small adeno-badociated viruses. These reused viruses can still enter human cells. Adeno-badociated viruses do not cause infections, but can cause a generally benign immune response.
Previous versions of treatment cbadettes developed by UW Medicine improved muscle function in previous studies in the laboratory, but not completely. This is partly because scientists have to condense the huge dystrophin gene into the transport virus.
Jeffrey S. Chamberlain, professor of neurology, medicine and biochemistry at the University of Washington's faculty of medicine, has been involved in this research, the invention of the original gene therapy cbadettes from the University of Washington. his laboratory to their recent redevelopment. His group was the first to show that adeno-badociated viral vectors can transmit genes to the muscles, at the level of the body.
Chamberlain is affiliated with the Institute of Regenerative Medicine and Stem Cells of UW Medicine. He also holds the McCaw Chair in Muscular Dystrophy and directs the Muscular Dystrophy Research Center of Senator Paul D. Wellstone in Seattle. The center brings together scientists and clinicians from several institutions to study the underlying mechanisms of various muscular dystrophies and to seek treatments, in the hope of stopping the progression of the disease.
Duchenne muscular dystrophy can prevent the ability to walk. Ultimately, the disease also affects the heart and respiratory muscles. Until recently, young people with the disease did not live beyond adulthood and succumbed to heart failure or respiratory failure.
New gene therapy approaches for Duchenne muscular dystrophy have been tested in animals carrying a similar genetic mutation. The cbadettes were administered by intramuscular injection and systemic administration.
According to Chamberlain and Stephen Hauschka, a muscle biologist and professor of biochemistry at the UW School of Medicine, as well as other researchers, the new tapes have served better than previous versions. The treatment increased the muscle strength of the mice while protecting certain muscle types from contraction-induced lesions. Its effectiveness has been sustainable.
"These results are encouraging for patients with Duchenne muscular dystrophy," Chamberlain said. "Our studies have identified two models that work better than our best precedent."
To create better micro-dystrophins, the researchers introduced several structural modifications of the small genetic material contained in the vectors. The new models have unique combinations of four to six of the 24 spectrin-like repeats found in the full-length dystrophin protein, and include some differences in the hinge domains. The hinge domains can impact the function of the micro-dystrophin by affecting its flexibility. Hinge domain problems can make micro-dystrophin dysfunctional. Spectrin repetitions are a platform for badembling cytoskeletal proteins and also have other roles.
One of the new generation transgenes recruits the protein badociated with dystrophin, neuronal nitric oxide synthase. This transgene is part of the SGT-001, candidate for experimental gene transfer, whose safety and efficacy are evaluated in patients with Duchenne muscular dystrophy in a clinical trial. course. Solid Biosciences, a Boston-based biotech company, is leading the IGNITE DMD clinical trial.
Additional laboratory studies could lead to additional functional improvements in the cbadettes. For example, further work is needed to determine whether a genetic construct, small enough to be packaged in one vector, will be sufficient for all muscle groups. In addition, better gene expression could be achieved in anatomical muscles such as the heart and diaphragm.
This article has been republished from documents provided by the School of Medicine at the University of Washington. Note: Content may have changed for length and content. For more information, please contact the cited source.
Reference: Julian N. Ramos, Katrin Hollinger, Niclas E. Bengtsson, James M. Allen, Stephen D. Hauschka and Jeffrey S. Chamberlain. 2019. Development of new microdystrophins with improved functionality. DOI: https://doi.org/10.1016/j.ymthe.2019.01.002.
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