A new technology for the genome editing of a wide range of mutations in living organisms



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A new technology for the genome editing of a wide range of mutations in living organisms

Targeted neuron using SATI technology. Credit: Salk Institute

The possibility of modifying genes in living organisms offers the possibility of treating a multitude of hereditary diseases. However, many types of gene editing tools do not help to target critical areas of DNA, and the creation of such a technology has been difficult because living tissues contain various types of cells.


Researchers at the Salk Institute have developed a new tool, called SATI, to modify the genome of the mouse, allowing the team to target a wide range of mutations and cell types. The new genome editing technology described in Cell search on August 23, 2019, could be extended to a wide range of gene mutation diseases such as Huntington's disease and the rare premature aging syndrome, progeria.

"This study showed that SATI is a powerful tool for genome editing," says Juan Carlos Izpisua Belmonte, professor at Salk's Gene Expression Laboratory and lead author of the article. "It could prove useful for developing effective strategies for replacing the target gene for many types of mutations and pioneering the use of genome editing tools to eventually heal a gene." wide range of genetic diseases. "

DNA-modifying techniques, including the CRISPR-Cas9 system, have generally been most effective at dividing cells, such as those in the skin or intestines, using DNA repair mechanisms. normal cells. The Izpisua Belmonte laboratory had previously shown that its CRISPR / Cas9-based gene editing technology, called HITI (for targeted integration independent of homology), could target both dividing and non-dividing cells. dividing cells. Protein coding regions function as recipes for making proteins, while regions called noncoding regions serve as a leader in determining the amount of food to be prepared. These non-coding regions make up the vast majority of DNA (~ 98%) and regulate many cellular functions, including gene activation and deactivation. They could therefore be a prime target for future gene therapies.

"We sought to create a versatile tool to target these non-coding regions of DNA, which would not affect gene function and would target a wide range of mutations and cell types," he said. said Mako Yamamoto, first author and postdoctoral fellow at the Izpisua Belmonte laboratory. "As proof of concept, we focused on a mouse model of premature aging caused by a mutation difficult to repair with the help of existing genome editing tools."

The new gene introduction method, called SATI (acronym for Intracellular Intercellular Intercell Intracellular Homology Intron-mediated Intron Targeting Integration), is an advance of the previous HITI method, which allowed it to target other areas of the genome. SATI works by inserting a normal copy of the problematic gene into the noncoding region of the DNA before the site of the mutation. This new gene then integrates into the genome alongside the old, via one of the many DNA repair pathways, which prevents the body from damaging the original mutated gene, without risking to damage its complete replacement.

The scientists tested SATI technology in live mice with progeria, caused by a mutation in the LMNA gene. Humans and mice with progeria show signs of premature aging, cardiac dysfunction and significantly shortened life expectancy due to the accumulation of a protein called progerin. Using SATI, a normal copy of the LMNA gene was inserted into the progeria mice. The researchers were able to observe a decrease in the signs of aging in several tissues, including skin and spleen, as well as a prolongation of the lifespan (45% increase over untreated progeria mice). A similar extension of lifespan, once translated for humans, would last more than a decade. Thus, the SATI system represents the first in vivo gene correction technology capable of targeting non-coding regions of DNA in several tissue types.

Next, the team aims to improve the effectiveness of SATI by increasing the number of cells incorporating the new DNA.

"More specifically, we will study the details of the cellular systems involved in DNA repair to further refine the SATI technology for better DNA correction," said Reyna Hernandez-Benitez, co-first author of the journal and postdoctoral fellow at Izpisua Belmonte. laboratory.


New CRISPR / Cas9 treatment can suppress aging


More information:
Keiichiro Suzuki et al, Accurate genome editing in vivo via the integration of an intron-targeting gene induced by a single-homology arm for the correction of a genetic disease, Cell search (2019). DOI: 10.1038 / s41422-019-0213-0

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Salk Institute

Quote:
A new technology for the genome editing of a wide range of mutations in living organisms (August 24, 2019)
recovered on August 24, 2019
at https://phys.org/news/2019-08-technology-genome-editing-broad-range-mutations.html

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