Targeted gene repair articles from across Nature Portfolio

The Template-Independent Genome Editing for Restoration (TIGER) platform enables efficient and precise correction of frameshift mutations in vivo, incorporates algorithms to score therapeutic guide RNAs and demonstrates restored hearing in a mouse model.

Engineered RNA base editors are powerful yet limited by promiscuous deaminase activity. Here, the authors devise RECODE that enforces target-dependent deaminase stabilization, thereby reducing off-target edits, and achieving effective in vivo editing of FUS and Angptl3.

In vivo base editing of a causative mutation that leads to the neurodevelopmental disorder Snijders Blok–Campeau syndrome restores protein dosage and ameliorates molecular and behavioural deficits in a humanized mouse model of the condition.

Linear donor DNA, including AAV, overactivates ATM in a copy-number-dependent manner, causing apoptosis and shifting repair toward c-NHEJ. ATM inhibition rescues high-donor cells and suppresses c-NHEJ, thereby increasing knock-in efficiency.

Although base editing has potential as a gene therapy tool, bystander edits limit its clinical use for many pathogenic mutations. This work uses directed evolution to optimize adenine base editors and 3′-extended guide RNAs to enhance targeting, producing more precise editors with reduced bystander effects.

We developed a customized base editing strategy to efficiently, precisely and safely correct the most common ACTA2 pathogenic mutation in multisystemic smooth muscle dysfunction syndrome. In vivo delivery of the bespoke base editor prolongs survival and rescues systemic phenotypes in a mouse model of multisystemic smooth muscle dysfunction syndrome.

We developed Dual Selective Organ-Targeting Lipid Nanoparticles (Dual SORT LNPs) capable of delivering base editors to multiple organs. Base editor Dual SORT LNPs corrected disease-causing mutations in both the liver and lungs, the primary organs affected in alpha-1 antitrypsin deficiency.

Two CRISPR tools harness DNA-dependent polymerases for genome editing — and may overcome some limitations of prime editors.