New CRISPR approach could improve gene and cell therapies

And what if CRISPR could be used not only to edit genes, but also to alter the epigenome – the vast network of chemicals and proteins that orchestrate gene actions? A biomedical engineering study from Duke University describes a new CRISPR technology that could enable scientists to do just that.

The most used gene editing technology, CRISPR-Cas9, uses a single protein case to cut DNA. In the CRISPR domain, it is a "class 2" system. Class 1 systems, on the other hand, are more complicated because they rely on several proteins to bind to the DNA, and then recruit a Cas3 protein to cut it. This protein network is called Cascade (complex associated with antiviral defense associated with CRISPR).

Duke's team used a class 1 CRISPR system to modify the epigenome in the cells. In a study published in Nature Biotechnology, they indicated that they were able to attach gene enhancers to the Cascade complex and regulate levels of gene expression in cells. They also connected a repressor to Cascade to completely disable the genes.

"We found that Cascade's structure was remarkably modular, allowing a variety of sites to attach enhancers or repressors, which are excellent tools for altering gene expression in cells "said Adrian Oliver, Ph.D., postdoctoral researcher author of the study, in a statement.

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The potential of CRISPR-Cas3 is already generating some interest in the biopharmaceutical world. In January, Locus Biosciences signed an agreement with Johnson & Johnson to develop its platform for using CRISPR-Cas3 to solve the problem of antibiotic resistance. The transaction could reach $ 818 million for Locus, a Fierce Group company established in 2019.

In parallel, several academic groups are studying various ideas to improve CRISPR, including another Duke team that is dedicated to improving the Cas9 enzyme. In April, he described a technique for adding a short tail to the guide RNA used in CRISPR systems to improve the precision of gene sections.

Researchers at Columbia University hope to completely avoid DNA cuts. They use a transposon, or "jump gene", in a system designed to insert DNA at specific locations in the genome without cutting.

Duke researchers, working on CRISPR class 1 technology, are planning further studies to determine if it could help solve some of the CRISPR-Cas9 weaknesses in the treatment of human diseases, including the risk of dangerous immune responses. They are also studying the possibility of using this tool to simultaneously perform many different genome engineering tasks.

"We know that CRISPR could have a significant impact on human health," said Charles Gersbach, Ph.D., professor of biomedical engineering at Duke. "But we are still at the beginning of understanding how CRISPR will be used, what it can do and what systems are available."