In vivo base editing alleviates hepatic iron accumulation and fibrosis in models of HFE-related hereditary hemochromatosis.

LNP-delivered adenine base editing corrected the HFE C282Y mutation in a murine iron-challenge model, achieving up to 67% in vivo conversion and reducing hepatic iron overload.

• Why it matters: HFE-related hereditary hemochromatosis from HFE loss-of-function can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma, and lacks causal therapies.
• What they did: Mice received LNPs carrying base editor mRNA and guide RNA for in vivo correction of HFE C282Y; cultured murine hepatocytes reached 73.6 ± 4.9% conversion, with next-generation sequencing showing no off-target effects with one or two mismatches.
• The result: Treated mice had significantly reduced hepatic iron overload despite continued high dietary iron intake, and transcriptomics showed decreased fibrosis and cancer signatures; patient-derived iPSC-derived hepatocyte-like cells had up to 63.8 ± 0.8% correction without detectable off-target activity.

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