The ability to process genes in living organisms offers the opportunity to treat a variety of hereditary diseases. However, many types of gene editing tools are incapable of targeting critical areas of DNA, and development of such technology has been difficult because living tissue contains different cell types.
Now, researchers at the Salk Institute have developed a new tool called SATI that can be used to process the mouse genome so that the team can target a wide range of mutations and cell types. The new genome editing technology described on August 23, 201
DNA Modification Techniques – In particular, the CRISPR-Cas9 system has generally been involved in the division of cells, such as cells. In the skin or gut, using the normal DNA repair mechanisms of the cells most effectively. The Izpisua Belmonte lab has previously shown that the CRISPR / Cas9-based gene editing technology called HITI (for homology-independent, targeted integration) can target both dividing and non-dividing cells. Protein-coding regions function like protein-making formulations, while regions called non-coding regions act as chefs, deciding how much food to prepare. These noncoding regions make up the majority of DNA (~ 98%) and regulate many cellular functions, including the switching on and off of genes. They could therefore be a valuable target for future gene therapies.
"We wanted to create a versatile gene tool to target those noncoding regions of DNA that would not affect the gene's function and to target a wide range of mutations and cell types," says Mako Yamamoto , Co-first author of the paper and a postdoc in the laboratory of Izpisua Belmonte. "As a proof-of-concept, we focused on a mouse model of premature aging caused by a mutation that is difficult to repair with existing genome-editing tools."
The New Gene Knock-In Method Scientists Call SATI (short for Intercellular Linearized Single Homology Arm Donor Mediated Intron-Targeting Integration) is a further development of the previous HITI method to address additional areas of the genome , SATI works by inserting a normal copy of the problematic gene before the mutation site into the noncoding region of the DNA. This new gene is then integrated into the genome along with the old gene via one of several DNA repair pathways, thereby relieving the organism of the deleterious effects of the original mutant gene, without the risk of damage if completely replaced.
The scientists studied the SATI technology in living mice with Progerie, which is caused by a mutation in the LMNA gene. Both humans and mice with progeria show signs of premature aging, cardiac dysfunction and drastically shortened lifespan 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 reduced signs of aging in various tissues, including the skin and spleen, as well as an increase in lifespan (45% more than in untreated Progeria mice). A similar lifetime extension, when applied to humans, would be more than a decade. Thus, the SATI system represents the first in vivo gene correction technology targeting non-coding DNA regions in multiple tissue types.
Next, the team wants to improve the efficiency of SATI by increasing the number of cells in which the gene is incorporated into new DNA.
"In particular, we will examine the details of cellular systems involved in DNA repair to further refine SATI technology for better DNA correction," said Reyna Hernandez-Benitez, co-lead author of the Papiers and a postdoc in the laboratory of Izpisua Belmonte.
A new CRISPR / Cas9 therapy can suppress aging
Keiichiro Suzuki et al., Accurate In Vivo Genome Processing via Single Homology Donor Mediated Intron Targeting Gene Integration to Correct Genetic Diseases, Cell Research (2019). DOI: 10.1038 / s41422-019-0213-0
A Novel Genome Processing Technology for a Variety of Mutations in Living Organisms (2019, August 24)
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