The molecular scissors correcting defective genes


CRISPR gene editing, based on the bacterial CRISPR-Cas9 antiviral defense system, is a breakthrough approach to editing genetic material in living organisms. In its simplest application, CRISPR-Cas9 acts as molecular scissors that can be used to precisely cleave or modify a DNA sequence of interest. Accurate, programmable and adaptable, this technology has found widespread application across several areas of biological and biopharmaceutical research.

CRISPR gene editing is routinely used in drug discovery, for example to generate accurate models of disease pathophysiology that were previously not possible. These models provide novel insights into disease and can also screen new drug targets before entering clinical trials.

However, the ultimate goal of gene editing is to be able to correct genetic material and treat the very source of congenital diseases. We are exploring the potential of using CRISPR to advance cell-based therapies that require precise gene editing as well as reversing disease pathophysiology in genetic diseases.


CRISPR is the most exciting life science discovery of the last decade. It is advancing our understanding of disease, has the potential to create ultra-sensitive diagnostics and as a medicine has the potential to enable the treatment of many genetic diseases.

Steve Rees Vice President, Discovery Biology, Discovery Sciences, R&D

In an early example, we demonstrated the use of CRISPR to reverse a mutation that causes a genetic enzyme deficiency in a humanised mouse model.1 Using CRISPR to remove the faulty DNA in a mouse model of the disease prevented the production of the defective protein and effectively eliminated one of the two main symptoms of the disease.

As part of our CRISPR toolbox, we are also designing – in collaboration with world-leading academic labs around the world – a range of innovative tools such as CRISPR GUARD2 , CRISPR VIVO3 and DISCOVER-Seq4 to establish the precision and safety of this technology and identify opportunities to develop future therapeutic applications.



References

1. Bjursell M, Porritt MJ, Ericson E, et al. Therapeutic Genome Editing With CRISPR/Cas9 in a Humanized Mouse Model Ameliorates α1-antitrypsin Deficiency Phenotype. EBioMedicine. 2018;29:104-111.

2. Coelho, M.A., De Braekeleer, E., Firth, M. et al. CRISPR GUARD protects off-target sites from Cas9 nuclease activity using short guide RNAs. Nat Commun 11, 4132 (2020). https://doi.org/10.1038/s41467-020-17952-5.

3. Akcakaya, Pinar, Maggie L. Bobbin, Jimmy A. Guo, Jose Malagon-Lopez, Kendell Clement, Sara P. Garcia, Mick D. Fellows, et al. 2018. “In Vivo CRISPR Editing with No Detectable Genome-Wide off-Target Mutations.” Nature 561 (7723): 416–19.

4. Wienert, Beeke, Stacia K. Wyman, Christopher D. Richardson, Charles D. Yeh, Pinar Akcakaya, Michelle J. Porritt, Michaela Morlock, et al. 2019. “Unbiased Detection of CRISPR off-Targets in Vivo Using DISCOVER-Seq.” Science 364 (6437): 286–89.




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