DC-PGE · DNA-binding domain Conditioned Precision Genome Editing

Genome editing in human therapies has the potential to revolutionize modern medicine. With numerous clinical trials underway and the recent approval of the first genome editing therapy, the field is rapidly advancing. However, there is a consensus that clinical genome editing tools must be efficient, precise and safe. Current tools predominantly rely on host cell DNA repair pathways to complete the editing process, which poses a risk for unintended editing events. Host cell DNA repair independent, fully programmable editing tools represent a new class of genome editing technologies, significantly expanding the potential for delivering life-saving therapies to patients. Genome editing tools that fulfil these characteristics are enzymes that recombine DNA. While there has been some success in engineering these enzymes to recognize and act on therapeutically relevant targets, their time-consuming and labour-intensive generation has hindered widespread implementation. DC-PGE aims to address this shortcoming. We have recently demonstrated that recombinase activity can be conditioned by internally fusing a zinc-finger DNA-binding domain into the enzyme's coding sequence, thereby making the enzyme activity contingent on zinc finger DNA binding. This pioneering discovery presents a genuine opportunity to develop next generation and best-in-class genome editing enzymes.DC-PGE aims to i) build a platform to apply DNA-binding conditioned precision genome editing to DNA-recombining enzymes, ii) develop a pan-recombinase system for immediate targeting of virtually any genomic sequence and iii) apply the technology to correct the genetic cause of MECP2 duplication syndrome at nucleotide precision. DC-PGE will serve as a foundation for advancing innovative treatments and improving patient outcomes. Our unique approach lies in combining different disciplines and cutting-edge technologies with the potential to transform the field of genome editing and elevate it to the next level.