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.
