Editorial: CRISPR and beyond: Cutting-edge technologies for gene correction in therapeutic applications.

Gene editing promises the ultimate cure for genetic diseases by directly correcting disease-causing variants. However, the first clinical trials have chased the “low hanging fruit” using editing strategies that rely on gene disruption by introducing double-strand DNA breaks that lead to insertions and deletions (indels) by the NHEJ pathway. Since NHEJ is constitutively active throughout the cell cycle and the default DNA repair pathway, this is by far the most efficient type of conventional gene editing as opposed to homology-directed repair (HDR). HDR relies on delivery of an exogenous repair template and this pathway is active only in the S and G2 phases of the cell cycle. These two parameters constitute challenges in clinical use of HDR since exogenous DNA is toxic in most therapeutically relevant cell types and since the inherent competition between NHEJ and HDR can be a bottleneck. However, HDR benefits from enabling precise edits to be made to the genome, thereby representing true gene editing with control over the outcome. Still, in both these modalities the DNA breaks are considered a potential source of genotoxicity due to the possibility of off-target edits and chromosomal aberrations such as translocations and chromothripsis. Next-generation gene editing tools like Base and Prime Editing that rely on DNA single strand nicking reduce the risk of such harmful events but are still limited in the scope of the edits they can generate (Anzalone et al., 2020). The newest types of editors based on CRISPR-associated transposases or CRISPR-directed integrases facilitate larger edits but are still under development and immature for clinical implementation (Yarnall et al., 2022; Tou et al., 2023). This rapidly developing toolbox is expected to broaden the application of CRISPR-based tools and other site-specific engineered nucleases to cure human disease. However, on this venture of realizing precise gene correction there are several unanswered questions and challenges to overcome, some of which we hope to address with this Research Topic on Therapeutic Gene Correction Strategies Based on CRISPR Systems or Other Engineered Site-specific Nucleases. This Research Topic covers a selection of contributions including significant scientific advances in precise genetic engineering as well as expert perspectives on recent advances. OPEN ACCESS