Co-written by:
Senior Director, Cell, Gene & RNA Therapy, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
SVP, Head of Research & Product Development, Alexion AstraZeneca Rare Disease
Gene editing offers new ways to treat diseases by precisely altering specific locations in the genome linked to disease. Explore our latest innovation, which represents a significant step forward in the potential to treat and cure genetic disorders.
Pursuing new frontiers in medicine with gene editing
Rare diseases, 80% of which are believed to have a genetic cause,1 are among the most promising applications for gene editing. By correcting the gene mutations that drive these serious health conditions, scientists aim to target their root causes and advance the potential for a curative therapy.
The CRISPR-Cas9 system is a well-known approach for gene editing. CRISPR technology has evolved since its discovery, and the scientific community continues to refine the approach to enhance accuracy and reduce the possibility of making unintended changes to other genes. CRISPR systems are both versatile and adaptable. They typically consist of gene editing machinery, which includes a guide ribonucleic acid (RNA) that locates the target gene and a Cas9 enzyme that acts like a molecular pair of scissors to correct the gene.
We are driven by our commitment to leverage promising genomic medicine approaches to address a range of diseases with significant need. In our quest to develop and improve new gene editing tools, we are building our own “CRISPR toolbox” containing new tools to enhance the potential of gene editing for therapeutic use.
Notably, we have identified a novel enzyme called PsCas9, a Cas9 variant renowned for its high precision and significantly reduced off-target effects.2 Through further optimisation, in collaboration with University of Texas at Austin, we have recently developed an even more robust and versatile engineered PsCas9 (ePsCas9).
Advancing gene editing with ePsCas9
ePsCas9 represents a significant advancement in our ability to edit genes with precision, in a field where accuracy is paramount for avoiding off-target effects. As highlighted in a study recently published in Nature Communications, ePsCas9 builds on the original PsCas9 with enhanced gene editing activity. The editing tools were encapsulated in lipid nanoparticles (LNPs), an innovative delivery system, which enables efficient delivery of the gene editing machinery to different organs and tissues.
LNPs are delivery vehicles that hold the potential to transport gene editing machinery into cells within target tissues. When appropriately designed, LNPs can carry the cargo to specific organs, and subpopulations of the cells within, making gene editing more versatile. In preclinical studies focused on the liver, we demonstrated that ePsCas9 can precisely target Pcsk9, a gene that helps to regulate cholesterol levels. While these findings demonstrate the ability of ePsCas9 to selectively edit genes in the liver, with further research and optimised delivery vehicles, ePsCas9 has potential applicability across numerous diseases.
ePsCas9 enhances the precision of gene editing by significantly reducing off-target modifications, making it a more reliable tool for correcting disease-causing mutations in DNA.
The future of gene editing to address unmet medical needs
The precision, programmability and adaptability of CRISPR has opened new horizons across diverse fields of biological and biopharmaceutical research. However, achieving high precision while maintaining the ability to edit a wide range of genes is a delicate balance that researchers continue to pursue. Over the last decade, various CRISPR-based tools have been developed that offer greater versatility, with the potential to tailor the approach to different therapeutic areas. The newly described ePsCas9, and delivery with LNPs, opens the door for the gene editing therapies of the future.
By improving the precision and delivery of gene editing, we open new possibilities for treating a wider range of rare, genetic disorders – many of which have few, if any, treatment options today. This journey is reflected in our efforts to combine AstraZeneca and Alexion’s expertise and resources to make meaningful impacts in genomic medicine to help improve the lives of people living with genetic disorders.
