Objective:

Assess liver gene correction and safety after LNP-delivered base editing in a patient with alpha-1 antitrypsin deficiency (AATD).

Approach:

• Study and treatment: Researchers assessed a 66-year-old man with Pi*ZZ AATD who received one intravenous 35 mg dose of investigational adenine base-editing therapy YOLT-202.
• Assessment: Ten weeks after treatment, a liver biopsy was analyzed for SERPINA1 editing, unintended genetic changes, and tissue health; circulating AAT and liver enzymes were also monitored.

Key Findings:

• The pathogenic SERPINA1 variant was corrected in 54% of alleles by Sanger sequencing and 57% by Illumina sequencing.
• No unintended changes were detected at nearby positions or at the predicted off-target sites examined.
• Circulating AAT rose from 0.15 g/L before treatment to 0.7 g/L at 10 weeks; functional testing showed elastase-inhibiting activity.
• Biopsy showed mild portal inflammation and fibrosis, with misfolded AAT aggregates in relatively few hepatocytes and no significant active liver injury.
• Liver enzymes rose transiently after infusion and normalized within two weeks.

Interpretation:

The authors report early clinical evidence of liver gene correction and functional AAT production 10 weeks after LNP-mediated base editing.

Limitations:

• The report describes one patient and a liver biopsy performed 10 weeks after treatment.
• The source states that larger clinical studies and longer follow-up are needed to determine whether the molecular changes provide lasting protection against liver and lung disease.

Conclusion:

The study provides an initial direct assessment of hepatic gene correction after LNP-delivered base editing in a patient with AATD.

Sources:

• Journal of Hepatology study (as described in the supplied context)