Reflecting the increasingly more targeted nature of drug development, AstraZeneca has formed four research collaborations involving CRISPR (clustered regularly interspaced short palindromic repeats), genome-editing technique, across its entire discovery platform in the company's key therapeutic areas. The technology will allow AstraZeneca to identify and validate new drug targets in preclinical models that closely resemble human disease. AstraZeneca will share cell lines and compounds with its partners and work with them to publish findings of its application of CRISPR technology in peer-reviewed journals, contributing to broader scientific progress in the field. The collaborations complement AstraZeneca's in-house CRISPR program and will build on the company's ‘open innovation' approach to research and development.

CRISPR is a genome-editing tool, which allows scientists to make changes in specific genes faster and in a more precise way than other methods. The technology has two components: a homing device to a specific section of DNA (guide-RNA) and enzymatic ‘scissors' that cut DNA (Cas9 nuclease). In the cell nucleus, the guide-RNA sequence directs the Cas9 nuclease to cause double-stranded breaks in the target DNA sequence. By harnessing the cell's own DNA-repair apparatus, the gene being targeted can be altered either by deleting it, adding nucleotides to it, or by turning its activity on or off. AstraZeneca says that in contrast to previous genome-editing techniques, such as zinc-finger nucleases and TALENs, CRISPR is easier to handle in the laboratory.

AstraZeneca's research collaborations are with the Wellcome Trust Sanger Institute (Cambridge, UK), the Innovative Genomics Initiative (IGI) (California), Thermo Fisher Scientific (Waltham, Massachusetts); and Broad Institute/Whitehead Institute (Cambridge, Massachusetts).

Under the terms of the collaboration with the Wellcome Trust Sanger Institute, research will focus on deleting specific genes relevant to cancer, cardiovascular, metabolic, respiratory, autoimmune & inflammatory diseases, and regenerative medicine to understand their precise role in these conditions. AstraZeneca will provide cell lines that can be targeted using the Sanger Institute's collection of genome-wide CRISPR guide-RNA libraries to generate populations of cells in which defined genes are switched off. Genes will subsequently be identified by next-generation sequencing and cell populations tested to validate the effects of a given gene on a wide range of physical and biological traits.

The IGI is a joint venture between the University of California, Berkeley and the University of California, San Francisco. The research collaboration will focus on either inhibiting (CRISPRi) or activating (CRISPRa) genes to understand their role in disease pathology. The IGI and AstraZeneca will work closely together to identify and validate gene targets relevant to cancer, cardiovascular, metabolic, respiratory, autoimmune, and inflammatory diseases and regenerative medicine to understand their precise role in these conditions.

Under the terms of the collaboration with Thermo Fisher Scientific, AstraZeneca will receive RNA-guide libraries that target individual known human genes and gene families. AstraZeneca can screen these guides against cell lines to identify new disease targets. The collaboration with the Broad Institute and Whitehead Institute will evaluate a genome-wide CRISPR library against a panel of cancer cell lines with a view to identifying new targets for cancer drug discovery. In addition to the new collaborations, AstraZeneca's in-house program is currently adapting CRISPR technology to streamline and accelerate the production of cell lines and translational models that mimic complex genomic and disease-relevant scenarios.

Source: AstraZeneca