Switch for "gene scissors"
Siberian scientists have invented a way to turn off the genome editing system at the right moment
Employees of the Institute of Chemical Biology and Fundamental Medicine SB RAS learned to inactivate the CRISPR/Cas9 genome editing system at a certain point in time and received a patent for their development. It allows you to turn off or block certain genes, for example, those that cause disorders in the nervous system and lead to various hereditary diseases.
The CRISPR/Cas9 system, or "genetic scissors", for the discovery of which in 2020 the American-French tandem of molecular biologists Jennifer Dudny and Emmanuel Charpentier received the Nobel Prize, can be used to correct mutations and helps treat hereditary diseases. However, this technology has a drawback — there is no way to stop the genome correction process at a certain time if you need to change not all DNA molecules, but only part of them. Diseases that cause damage to the nervous system are often associated not only with the presence of an unhealthy gene, but also with its duplication or multiplication — an increase in the number of copies. With the help of a modified guide RNA, which was proposed as a solution by the scientists of the IHBFM SB RAS, it becomes possible to rid a person of some diseases caused by such a feature. It is necessary to make one copy non-working, but leave the second one unchanged. The system is targeted at this gene and turned off after it performs the desired action. For this purpose, the CRISPR/Cas9 photo-switching method was developed.
"The genomic editing system is a nucleoprotein complex consisting of two components: protein and nucleic acid — RNA. RNA addresses a protein to a specific DNA fragment in order to split it in the desired location. The guide RNA that we have created contains photo—cleavable linkers - special chemical compounds that are sensitive to light. When irradiated with soft ultraviolet light at a given time, they inactivate RNA, while disabling the genomic editing system at the desired time point. This makes it possible to block the system and leave the second copy of DNA intact. Since it is practically impossible to irradiate nerve cells inside the body with light, the system can be used in ex vivo format (outside the body): a part of the cells is taken from the patient, the genome is edited in a test tube, and then returned back," says the author of the patent, senior researcher at the Laboratory of RNA Chemistry of the IHBFM SB RAS, Candidate of Chemical Sciences Daria Sergeevna Novopashina.
With the help of modified guide RNA, it becomes possible to develop therapeutic agents for the treatment of certain hereditary, genetically determined diseases: for example, Charcot—Marie—Tutt syndrome, which affects the peripheral nervous system and leads to deformity of the feet and hands, weakness and atrophy of the muscles of the extremities.
Researchers believe that in the future, using editing technology will open up ways to influence chromosomal pathology — Down syndrome. "The destruction of an extra chromosome is a serious and global task, we have not yet found a solution to this problem. But theoretical steps in this direction are quite real," notes D. S. Novopashina.
In 2019, researchers from the IHBFM SB RAS received a grant from the Russian Foundation for Basic Research to study gene regulation, in 2022 a grant from the Russian Science Foundation, and also registered a patent for "A modified guide RNA with the ability to inactivate the CRISPR/Cas9 genome editing system and a method for obtaining it."
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