Applications of Latest-Generation Base Editors in the Correction of Point Mutations Causing Neonatal Diabetes
Year: 2025
Type: article
Abstract: CRISPR-based genome editing has emerged as a powerful and promising tool for treatment of monogenic diseases which lack effective clinical therapies, with several CRISPR-based gene therapies nearing market approval. Developments in the field have generated safer and more widely applicable genome editing tools, including base editors which can catalyze single-nucleotide changes without breaking the DNA backbone. Researchers have optimized these base editors to make them increasingly efficient in editing and allow them to bypass previous restrictions in accessing certain genomic regions -- base editors known as ABE8e-SpRY and CBE4max-SpRY are two of these latest-generation base editors. Work done within the Otonkoski-Balboa group has led to the characterization of three point mutations which cause neonatal diabetes and are attractive candidates for latest-generation base editors as they lack curative therapies and are difficult to access using previously available base editors. To evaluate the potential of ABE8e- and CBE4max-SpRY to correct the disease-causing point mutations, stem cells and fibroblasts containing the mutations were transfected with the base editing systems and genotyped to quantify the degree of editing. Optimized synthetic gRNA in combination with an optimized ABE8e-SpRY base editor was capable of catalyzing highly efficient editing in positive control sites within a small editing window compared to previous iterations of these tools. Promising results were observed for one of the disease-causing mutations, however editing of the other two disease-causing mutations using ABE8- and CBE4max-SpRY was unsuccessful. Further experimentation with improved components could yield positive results for eventual use in diabetes-curing therapies for individuals carrying these mutations.
Source: Työväentutkimus Vuosikirja
Author: Huhdanpää, Sonja
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7199713418