Written by:
Senior Director, Cell, Gene & RNA Therapy, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
VP of Genomic Medicine at Alexion, AstraZeneca Rare Disease
80% of rare diseases are associated with underlying genetic causes. Gene therapies have the potential to treat the underlying cause of many rare diseases. Explore our most recent publications in Nature Communications to learn how we’re continuing to refine the precision, safety profile and versatility of gene editing technologies with the aim of better serving patients.
DNA is the most intricate instruction manual ever written and editing it with precision requires a range of tools. No single gene editing method can be used to address the wide spectrum of disease-causing mutations. Our scientists are developing diverse gene editing tools that can be used as potentially curative treatments for people living with diseases with a genetic cause. While tremendous progress has been made, we continue to refine these tools to expand their reach, improve their precision and unlock the potential for therapies with enhanced safety.
Refining the tools to precisely edit DNA
We are investigating the potential of prime editing technology, a powerful approach that allows scientists to rewrite small sections of DNA. In 2022, we developed the Prime Editor nuclease (PEn) system which is a gene editing approach that allows efficient gene insertions to correct genetic mutations. 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.
Two new studies published in Nature Communications expand on this work by further refining prime editing technology with the goal of translating this technology to clinical applications.
Building upon prime editing to advance genomic medicines
In the first study, our scientists designed a strategy to reduce potential undesired gene edits during the prime editing process. This strategy works by modifying the pegRNA, effectively inserting a “stop sign” so that the guide RNA scaffold sequence itself is not copied and incorporated into the desired edit. This enhancement helps avoid introducing unintended sequences to the genome, facilitating more accurate edits to the targeted gene.
In the second study, we demonstrated that a new approach, called 2 inhibitor prime editing (2iPE), can increase specificity and safety of prime editing technologies in a simple way. This method, which can be applied broadly across different prime editing systems, works by temporarily blocking two enzymes, DNA-PK* and Polθ**, with small molecule using pharmacological inhibitors, to boosting PEn the precision of prime editing up to 9.8 fold. This approach can be applied broadly across different prime editing systems, supporting the potential use of this approach for diverse clinical applications in the future.
Looking ahead
While these studies help advance gene editing, we’re committed to building upon and refining these approaches to address the underlying causes of many rare diseases. Doing this brings us one step closer to our larger goal of delivering medicines that can potentially change the course of disease. By developing precise gene editing technologies with enhanced safety and efficacy, we are helping pave the way for genomic medicines that have potential to correct the root cause of disease while delivering lasting impact for patients.
[Abbreviations] *DNA-PK=DNA-dependent Protein-Kinase **Polϴ=DNA polymerase ϴ
