RNA editing tool can take some of the risk out of gene therapy

The ability to correct pathogenic genetic errors using genome publishers is very promising in medicine, but it is not without risk. When this type of “genetic surgery” is carried out on DNA, for example, there is always the danger of leaving permanent genetic scars which can even be hereditary.

To alleviate this risk, researchers have experienced the gene editing processes on messenger RNA (mRNA), a central link between DNA and proteins that does not include the same risks because it does not imply permanent DNA changes. But existing RNA editing tools have been too heavy to use or too toxic to human cells.

Yale researchers have developed a new family of RNA publishing tools that use RNA targeting activity they found “hidden” in a popular gene editing tool known as Crispr-Cas9.

“The solution was surprisingly simple,” said the main study of the study, Ailong Ke, professor of molecular biophysics and biochemistry at the Yale School of Medicine and member of the Faculty of Arts and Sciences of Yale. “We discovered a robust activity of hidden RNA target inside [the CRISPR tool] And its related enzyme, ISCB, and simply triggered its hidden power to target the RNA. “”

Their results are published in the journal Cell.

The CRISPR (rewarded the regularly intertwined palindromic rehearsals) are DNA sequences found in the genomes of organisms – such as bacteria and archaea – whose cells have no nucleus and other organelles linked to the membrane. CAS9 (Protein 9 associated with CRISPR 9) is an enzyme that uses CRISPR sequences. CAS9 enzymes and CRISPR sequences form the basis of CRISPR-CAS9 technology used to edit genes in living organisms.

The approach was guided by “a deep understanding of the molecular structures of the ISCB”, including the results reported by the laboratory in the journal Science, said Chengtao Xu, postdoctoral partner with Yale and the first author of the study.

“It would be much more difficult to find the same idea of Cas9, because its structure is much more sophisticated than the ISCB,” said Xu. “Nature leaves us a lot of treasures, and it is difficult but intriguing to reveal them. This is something in which we are particularly good in molecular biophysics and biochemistry.”

The researchers have appointed their new R-ISCB and R-CAS9 tools and have defined their use in genome research and medicine.

“These are the Swiss army knives for the RNA edition,” said Ke. “We show that they can be used to disturb the functions of the mRNA, to decide and destroy the targeted mRNA, or to correct coding errors in the target of the mRNA.

“In essence, we have a way to perform any type of genetic surgery in the RNA, which is a big problem.”

Xu added that the tools operated both on Cas9 enzyme targets, which use CRISPR sequences. “We are really delighted to see how far we can adopt this approach with other similar tools,” he said.

Researchers now plan to test laboratory tools to cure rare genetic diseases or to promote the healing of wounds.

“We are particularly enthusiastic about the sweating reactions made by R-ISCB, because it can potentially correct any type of genetic mutations at RNA. This is a huge opportunity for genome medicine,” Ke said.

“There are many potential applications. The new tool is robust, very precise and quite versatile.”

The other authors of the study include Xiaolin Niu and Haifeng Sun, who are postdoctoral partners in Yale. The study also involved the employee, Professor Weixin Tang at the University of Chicago.