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Using CRISPR to identify drug targets
AstraZeneca collaborated with the Wellcome Sanger Institute, providing access to its CRISPR libraries. These libraries are a collection of CRISPR reagents with a set of attached gRNAs, each designed to edit a specific part of the human genome.
Through these libraries, scientists can alter the activity of genes in a biological pathway, which could provide a detailed understanding of gene function and genetic causes of disease, which would help identify the genes. targets of the disease.
In addition, scientists can also observe genetic changes that underlie disease pathways by disabling (disabling) genes or activating them with technologies known as CRISPRi and CRISPRa screens (inhibitors and enhancers). .
Scientists can then examine the effects of this change and discover potential therapeutic targets for diseases.
To achieve this goal, AstraZeneca is also partnering with the Institute for Innovative Genomics (IGI) to develop CRISPR libraries with CRISPR displays.
Luke Gilbert, an badistant professor in the Department of Urology, at the Helen Diller Family Comprehensive Cancer Center and at the IGI of the University of California at San Francisco, explains how CRISPR-focused collaboration continues work on DNA damage response (DDR), a key platform in oncology.
"Our collaboration with AstraZeneca involves the use of CRISPRi or CRISPRa screens (inhibitors or activators) to activate or deactivate all genes in the genome, which helps to understand how this contributes to the biology of the repair of the genome. DNA, "said Gilbert.
"In normal development, DNA is frequently damaged on a large scale, resulting in genome alterations that can cause cancer (pro-oncogene) or cause tumors (pro-tumorigenic), which ultimately leads to cause the disease. progression.
"Normal cells repair the DNA very effectively, but this is interrupted by the biology of cancer. So we want to know how it is, how we can manage it and how we can target it therapeutically.
"Our goal is to take individual patient genomes and examine them, then ask ourselves how to use new drugs, or new drug combinations, to target this DNA repair process accurately and safely." .
"To do this, we use a nucleus that is essentially an effective form of Cas9 that does not cut DNA but instead allows us to provide proteins that turn on or off gene expression at will."
However, CRISPR libraries are not exclusively for oncology. AstraZeneca has confirmed that it applies this technology in other therapeutic areas, including cardiovascular, renal, metabolic and respiratory diseases, with the goal of investigating new pathological targets.
CRISPR can also be used to recreate human genetic diseases by modifying the DNA of animals and cell lines. This more relevant model for the disease can then be used to quickly test drug candidates.
Until now, AstraZeneca has been able to produce more than 120 cell models in order to improve the understanding of disease pathways with CRISPR.
She has also successfully produced models of transgenic mouse disease in record time of two months, instead of ten months with traditional methods.
The potential of CRISPR as a target drug identification tool is enormous, but what about its use as a therapeutic tool? Although AZ has not completely excluded it, the potential presents several challenges.
"It's very difficult to consistently provide CRISPR treatment in the right place, especially if there are easier ways to do it, such as CAR-T treatment," says Pangalos.
"But with CRISPR, if you have to change something in every muscle cell or in every mutated tumor cell, how do you exactly? It's not easy. "
Among the complications during childbirth, there are also issues of editorial specificity and ethical issues, but that does not mean that CRISPR as therapy will no longer be viable in the future.
For now, however, AstraZeneca intends to become a leader in CRISPR drug discovery, and strengthening its partnerships in Cambridge will enable it to realize its vision of an R & D revolution.
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