Duchenne typically occurs through one mutation in a gene called dystrophin, which makes a protein with the same name. In people without the disease, the dystrophin protein helps strengthen and connect muscle fibers and cells. There are hundreds of mutations in the dystrophin gene that can lead to the disease, but in 60 percent of people with Duchenne, their mutation will occur within a specific hot spot of the gene.
Duchenne mutations cause abnormally low production of the dystrophin protein, which in turn causes muscles to degenerate and become progressively weaker. Symptoms usually begin in early childhood; patients gradually lose mobility and typically die from heart or respiratory failure around age 20. Some current medications can treat the disease’s symptoms but none can stop the progression of the disease or significantly improve patients’ quality of life — and there is currently no way to reverse or cure the disease.
To test the platform, they obtained skin cells from consenting patients at the Center for Duchenne Muscular Dystrophy, all of whom had mutations that fell within the dystrophin gene hot spot. The researchers reprogrammed the cells to create induced pluripotent stem cells in an FDA-compliant facility. Induced pluripotent stem cells, or iPS cells, have the ability to become any type of human cell while also maintaining the genetic code from the person they originated from.
Next, the scientists removed the Duchenne mutations in the iPS cells using a gene editing platform they developed that uses the CRISPR/Cas9 technology. (CRISPR stands for “clustered regularly interspaced short palindromic repeats.”) The platform targets and removes specific regions of the hot spot of the dystrophin gene, which harbors 60 percent of Duchenne mutations, which restores the missing protein.
Once the UCLA researchers had produced iPS cells that were free from Duchenne mutations, they differentiated the iPS cells into cardiac muscle and skeletal muscle cells and then transplanted the skeletal muscle cells into mice that had a genetic mutation in the dystrophin gene.
They found that the transplanted muscle cells successfully produced the human dystrophin protein. The result was the largest deletion ever observed in the dystrophin gene using CRISPR/Cas9, and the study was the first to create corrected human iPS cells that could directly restore functional muscle tissue affected by Duchenne.
https://www.stemcell.ucla.edu/news/promising-duchenne-study
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