Adenine base editing reduces misfolded protein accumulation and toxicity in alpha-1 antitrypsin deficient patient iPSC-hepatocytes

Alpha-1 antitrypsin deficiency (AATD) is most commonly caused by the Z mutation, a single-base substitution that leads to AAT protein misfolding and associated liver and lung disease. In this study, we apply adenine base editors to correct the Z mutation in patient induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iHeps). We demonstrate that correction of the Z mutation in patient iPSCs reduces aberrant AAT accumulation and increases its secretion. Adenine base editing (ABE) of differentiated iHeps decreases ER stress in edited cells, as demonstrated by single-cell RNA sequencing. We find ABE to be highly efficient in iPSCs and do not identify off-target genomic mutations by wholegenome sequencing. These results reveal the feasibility and utility of base editing to correct the Z mutation in AATD patient cells.

Automated summary

This study demonstrates the feasibility and effectiveness of using adenine base editing to correct the Z mutation in AATD patient cells, reducing abnormal protein accumulation and improving secretion, as well as decreasing ER stress in edited cells. Adenine base editing is highly efficient in iPSCs and does not result in off-target genomic mutations, as shown by whole-genome sequencing.