The genes management technique, known as CRISPR, is a revolutionary approach to the treatment of hereditary diseases. However, the tool has not yet been used to treat long-term, chronic conditions effectively. The research team, led by dr. Dongsheng Duan, of the University of Missouri School of Medicine, has identified and overcome an obstacle in regulating the CRISPR gene that can lay the foundations for sustained treatment using the technique.
The regulation of the CRISPR gene is inspired by the natural defensive ability of the body to prevent viruses. The technology allows researchers to change the DNA sequence by cutting out and replacing a mutation in a genome that has the potential to treat a variety of genetic diseases and conditions. Duan, together with his colleagues at the MU, the National Center for the Advancement of Translational Sciences at the National Institute of Health and the University of Duke, are studying how to use CRISPR to treat Duchenne Muscular Dystrophy (DMD).
Children with DMD have a gene mutation that interrupts the production of a protein known as dystrophin. Without dystrophy, the muscle cells become worse and eventually die. Many children lose the ability to walk, the muscles needed for breathing and functioning of the heart, but eventually stop working.
"CRISPR essentially cuts the mutation and reconverts the gene," said Duan, who is Professor Margaret Proctor Mulligan for medical research at the Department of Molecular Microbiology and Immunology at the Medical Faculty of the MU. "In order to achieve this," CRESPR molecular scissors "known as Cas9 must know where to cut and the location for cutting is a molecule called gRNA. In our mouse model, the effectiveness of the therapy could be extended from three months to 18 months. "
Duan's laboratory treated 6-week mice with DMD intravenously using CRISPR and looked for improvements at 18 months. Initially they used a strategy that many researchers used. In this approach, similar amounts of Cas9 and gRNA were administered. While it worked well when injected directly into the muscle, this strategy produced poor results when the team tried to achieve the long-term elimination of all muscles in the body. Dystrophic regeneration in skeletal muscles and the restoration of low levels of dystrophin in the heart were not detected – treatment failed to stop the progression of the disease.
When reviewing the results, the group found a disproportionate depletion of the gRNA flag, which means that there was not enough gRNA to tell Cas9 where to cut it. The team increased the number of gRNA flags and repeated the attempt. This new strategy significantly increased the recovery of dystrophin in cardiac and skeletal muscles and reduced muscle wasting after 18 months. In addition, muscle function and cardiac function improved.
"Our results show that the loss of gRNA is a unique obstacle to long-term systemic treatment with CRISPR," Duan said. "We believe this barrier can be overcome by increasing and optimizing gRNA doses. Although this has an interesting potential for improving DMD treatment, we believe that this principle can also be used for other CRISPR treatments for a range of other diseases and conditions."
Researchers will continue to test and perfect the approach in the mouse model before other models are explored. Several studies hope that this insight could help lay the foundations for better therapy with the assembly of the CRISPR genes.
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