Improving gene-editing efficiency for many different mutations
We propose to improve precise gene-editing efficiency for many currently difficult-to-edit mutations by optimizing the gene-editing tools by combining scientific gene-editing (UMCU) and structural RNA (RUG) expertise with industrial biosynthesis capacity (Trilink).
In the Netherlands, >10.000 families are affected by genetic metabolic diseases. These rare diseases cause significant child morbidity and mortality. When considering the whole group of rare genetic diseases, these are estimated to affect >30 million people in Europe and cost $1 trillion per year. Efficient therapies are sorely lacking. Recent progress in precise gene-editing technologies now opens the avenue for gene-correction therapies, but gene-editing efficiency remains insufficient for the majority of disease-causing mutations.
We aim to improve prime-editing efficiency for the large variety of mutations by modifying the prime-editing tools to improve the interaction between the prime-editing guide RNA (pegRNA) to the prime editor and the DNA. Based on the results, we will develop an AI-tool to optimize pegRNA-design for any DNA-target. We will then test in vivo delivery and effects of these modifications in the prime-editing tools. This will lay the basis for developing gene-correction therapies for the many different disease-causing mutations.
As concrete deliverables, we will optimize prime-editing tools for clinically relevant mutations that are currently difficult to correct in our laboratory. If successful, this will propel our gene-correction-therapy program for our patients. We will use resulting insights in pegRNA-design and composition to generate a self-learning AI-tool to rapidly design the optimal pegRNA for any mutation. This can result in innovative pegRNA-designs that may revolutionize any gene-editing application. Finally, we will deliver the modified prime editors in vivo to test the effects and safety of modified prime editors as a proof of concept for clinical application of optimized prime-editing therapies. Resulting therapies may alleviate the suffering of countless individuals with a spectrum of disorders.
