CRISPR gene editing has promised to revolutionize genetics and medicine. But it has limitations. Researchers with the Salk Institute developed a new type of gene editing called SATI that may provide the option of editing numerous gene mutation diseases like Huntington’s disease and the rare premature aging syndrome, progeria.
SATI stands for intercellular linearized Single homology Arm donor mediated intron-Targeting Integration. It is an advanced form of another type of gene editing tool called HITI (homology-independent targeted integration).
CRISPR is typically most effective in dividing cells, like those found in the skin or gut, because it leverages the cells’ DNA repair mechanisms. Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory, had previously developed HITI, which is a modification of CRISPR, that could target both dividing and non-dividing cells.
There are, broadly, two types of regions in the genome—protein-coding regions, where the DNA codes specifically for proteins, and non-protein-coding regions, which regulate many cellular activities, turning genes on and off. The non-coding regions actually make up about 98% of the genome.
“This study has shown that SATI is a powerful tool for genome editing,” stated Izpisua Belmonte, senior author of the latest study. “It could prove instrumental in developing effective strategies for target-gene replacement of many different types of mutations and opens the door for using genome-editing tools to possibly cure a broad range of genetic diseases.”
SATI functions by inserting a normal copy of the malfunctioning gene into the non-coding region of the DNA before the site of the mutation. It is integrated into the genome alongside the old gene by way of one of several DNA repair pathways. It then decreases the abnormal effects of the original, mutated gene without risking damage connected with completely replacing it.
They evaluated SATI in living mice with progeria, caused by a mutation in the LMNA gene. In both mice and humans with progeria, they have premature aging, cardiac dysfunction and significantly shorter life spans due to the accumulation of the progerin protein. Using SATI, they inserted a normal copy of the LMNA gene into the mice. The aging symptoms decreased, including skin and spleen, and the mice’s life span increased 45% compared to the untreated progeria mice. If compared to humans, that would extend life by more than a decade.
They plan to work to make the technique more efficient by increasing the number of cells that can incorporate the new DNA.
“Specifically, we will investigate the details of the cellular systems involved in DNA repair to refine the SATI technology even further for better DNA correction,” said Reyna Hernandez-Benitez, co-first author of the paper and a postdoctoral fellow in the Izpisua Belmonte lab.
The research was published in the journal Cell Research.
“We sought to create a versatile tool to target these non-coding regions of the DNA, which would not affect the function of the gene, and enable the targeting of a broad range of mutations and cell types,” stated Mako Yamamoto, co-first author and postdoctoral fellow in the Izpisua Belmonte lab. “As a proof-of-concept, we focused on a mouse model of premature aging caused by a mutation that is difficult to repair using existing genome-editing tools.”