Written by:
Senior Director, Cell, Gene & RNA Therapy, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
VP of Genomic Medicine at Alexion, AstraZeneca Rare Disease
Advances in gene editing technologies are helping improve the precision, safety profile and versatility of genomic medicines. Through innovations in prime editing and enhanced approaches, we are working to unlock the potential of gene therapies to address the underlying causes of genetic diseases and aim to deliver lasting benefit for patients.
80% of rare diseases are associated with underlying genetic causes, making genomic medicine a powerful approach for treating a wide array of rare diseases.1
As we gain a deeper understanding of biology behind more of these genetic diseases, the advancement of gene editing technologies is accelerating. Our most recent publications in Nature Communications capture how we are continuing to refine the precision, safety profile and versatility of these technologies, with the aim of delivering lasting benefit to patients.
Refining the tools to precisely edit DNA
We are investigating innovative ways to advance the potential of templated editing technology, a powerful approach that allows scientists to rewrite small sections of DNA.
We developed the Prime Editor nuclease (PEn) system, a gene editing approach that enables efficient gene insertions with a reduced risk of unintended large deletions.2 A part of this engineered system, called the prime editor guide RNA (pegRNA), ‘guides’ an enzyme (spCas9) to the part of the genome needing repair. The enzyme then acts as a pair of molecular scissors to cut the editing site while a second enzyme (reverse transcriptase) helps write in the correct sequence to repair the gene.2
Building on this, we have gained insights in designing guide RNAs to help avoid introducing unintended sequences to the genome, facilitating more accurate edits to the target gene.3 Most recently, we demonstrated that small molecule inhibitors can boost editing specificity up to 9.8-fold.4 Together, these advances lay the groundwork to help translate gene editing technology into clinical applications.
Characterising editing outcomes to enhance the safety profile of genomic medicines
Precise gene editing is one part of the equation. Equally important is how we characterise editing.
Analytical methods assess large populations of cells together, providing a valuable, but averaged, view. Our latest research helps to refine the analytical lens, examining editing outcomes cell by cell rather than across millions of cells at once.
This research revealed that individual cells each carry their own unique editing profile, a level of detail that is invisible to conventional bulk analysis. Our single-cell approach uncovered editing events not detected using standard methods, demonstrating a richer, more complete picture of how gene editing tools interact with the genome.
We further observed that editing outcomes varied depending on cell and tissue type, highlighting the importance of testing gene editing tools specifically in the target cell type to help more accurately predict therapeutic outcomes.
We also found that unintended edits are more likely to occur in DNA regions that are more active and accessible. Factors such as the local chromatin environment and DNA methylation patterns influence where and how editing occurs. Together, these results illustrate the context-dependent nature of gene editing outcomes, which has implications for helping to improve how these technologies are designed, evaluated and optimised for clinical use.
Looking ahead
We’re committed to continuing to refine these approaches to address the underlying causes of genetic diseases. By developing precise gene editing technologies with enhanced safety profile and efficacy, we are moving one step closer to our larger goal of delivering genomic medicines that have the potential to correct the root cause of disease while delivering lasting impact for patients.
