Genome-Wide CRISPR Screen Identifies Two Human Genes That Boost Nonviral Editing

Overview

• A University of Wisconsin–Madison team used a pooled CRISPR knockout screen of about 19,000 human genes to find cellular factors that limit nonviral genome editing.
• The six-year project narrowed 26 candidate genes to two validated top hits, GJB2 and BET1L, whose depletion raised base-editor efficiency by more than sixfold in cell models.
• In patient-derived retinal cells from people with Leber congenital amaurosis, inhibiting GJB2 or BET1L increased editing efficiency by more than 3.5 times using lipid-nanoparticle delivery.
• The improvements held across multiple genomic targets and across lipid-based delivery of both Cas9 nucleases and base editors, showing the effect is not limited to one editor or cargo type.
• Authors frame the result as a shift from only improving delivery vehicles to transiently conditioning host cells, a strategy that could affect mRNA vaccines and other lipid-nanoparticle therapies but requires mechanistic work and in vivo safety testing before clinical use.