肌肉萎缩症,基因编辑,CRISPR z-bo 2020-09-21 443

　　Three research teams used CRISPR to cut out part of the defective gene in mice with Duchenne muscular dystrophy (DMD), allowing these rodents to make an essential muscle protein. This method is the first time that CRISPR has been successfully used to treat a genetic disease in adult animals.

　　The hot genome editing tool CRISPR has achieved another achievement-researchers used it to treat a severe muscular dystrophy in mice.

　　DMD is caused by dystrophin deficiency or impaired function. Dystrophin is an important part of muscle. Its gene contains 79 protein coding regions called exons. Mutations in any one exon may cause dystrophin problems. DMD only affects boys, about 1 in 3,500 newborn boys suffers from the disease, and patients usually only live to their 30s.

　　So far, researchers have not found a way to effectively treat this disease. It has proven difficult to provide enough muscle stem cells to enter the correct tissue to prevent this disease from occurring. Traditional gene therapy-using a virus to carry a good version of the damaged gene into the cell-cannot replace the complete dystrophin gene, because the latter is too big. Some gene therapy experts hope to provide DMD patients with a "micro" dystrophin gene, which will bring a short but working protein to reduce the severity of the disease. Some companies have developed compounds that allow the cell's DNA reading mechanism to bypass a defective exon of the dystrophin gene, resulting in a short but functional key protein. But these so-called exon-skipping drugs have not convinced regulators because they have side effects and can only slightly improve muscle performance in clinical trials.

　　Now, CRISPR has entered people's field of vision. This technology, which was named a 2015 Breakthrough by Science magazine, relies on a single-stranded RNA to guide an enzyme called Cas9 to precisely locate in the genome and then cut DNA. The cell then repairs the gap by connecting a damaged strand or creating a new sequence using a provided DNA template. Scientists have used CRISPR technology to correct certain genetic diseases in cells collected from animals or humans, and successfully treated liver diseases in adult mice. In 2014, researchers discovered that this technique can also repair the defective dystrophin gene in mouse embryos.

　　But it seems impractical to use CRISPR to treat patients with DMD, because mature muscle cells in adults usually do not divide and therefore do not have the DNA repair mechanism necessary to initiate the process of adding or correcting genes. But CRISPR can be used to snip a defective exon so that the cell's gene reading mechanism can create a shortened version of dystrophin, similar to exon skipping and minigene methods.

　　In the first study, Charles Gersbach, a biomedical engineer at Duke University in Durham, North Carolina, and others used CRISPR to delete the mutated exon 23 and trigger the body to automatically "sew" the remaining protein coding regions to make A new version of dystrophin that is shortened but still works.

　　They first used the non-pathogenic adenovirus as a vector to deliver the gene editing system into the leg muscle cells of adult mice. The results showed that the level of dystrophin in the legs was restored to a certain extent and muscle strength increased. They injected the gene editing system into the blood of mice. This time, the muscles of the mice were improved, especially the muscles related to the heart. Myocardial failure is one of the main direct causes of death in DMD patients.

　　In two other studies, Chengzu Long of the University of Texas and Amy Wagers of Harvard University also used a combination of adenovirus and gene editing technology to treat mice with DMD and found that the muscle function of the mice had similar improvements.

　　Gersbach commented: “Although there is still a lot of work to be done to convert this method into a human therapy and verify its safety, the results of our first batch of trials are exciting.”

　　He emphasized that although there are ethical controversies in the academic circles about whether the gene editing technology can modify the mutant genes of human embryos, there is no controversy about using the technology to correct the genetic mutations in the affected tissues of patients.

　　This has encouraged other muscular dystrophy researchers. Jerry Mendell of the Jerry Mendell National Children’s Hospital in Columbus said: “This seems to be a very promising treatment clinically.” Ronald Cohn at the Children’s Hospital of Toronto, Canada emphasized: “One of the questions we all had was the CRISPR gene. Whether editing can happen in living skeletal muscle." He said that the new research is "an exciting advancement."

　　CRISPR technology has been selected as one of the Top Ten Breakthroughs of Science for three consecutive times in the past three years since its introduction. In 2015, it was named the number one breakthrough. The magazine believes that the high precision, low cost, and easy operation of gene editing technology is bound to have a "revolutionary impact" on research.