In vivo base editing rescues liver pathophysiology and peroxisome dysfunction in a mouse model of Zellweger spectrum disorder - PubMed
3 hours ago
- #gene editing
- #peroxisome disorder
- #mouse model
- Zellweger spectrum disorder (ZSD) is caused by loss-of-function variants in PEX genes, affecting peroxisome biogenesis and leading to liver disease and neurological issues.
- A mouse model with the PEX1-p.G844D mutation, similar to human ZSD, was treated using adenine base editing via AAV9 delivery, achieving up to 60% allele correction in liver.
- Base editing normalized fatty acid and bile acid levels, restored peroxisome function, and improved liver histopathology and body weight in treated mice.
- Non-viral lipid nanoparticle delivery of base editing mRNA also achieved 27% correction in liver cells, showing alternative delivery methods are viable.
- In human patient-derived fibroblasts, base editing corrected over 80% of PEX1-p.G843D alleles and restored peroxisome homeostasis.
- Off-target analyses indicated minimal unintended editing, supporting the safety and specificity of the base editing approach for potential therapeutic use.