AI Insight
A 66-year-old patient with alpha-1 antitrypsin deficiency received in vivo base editing gene therapy that successfully corrected the disease-causing mutation in approximately 54-57% of liver cells, as confirmed by liver biopsy ten weeks after treatment. The procedure showed no signs of inflammation, off-target effects, or concerning tissue changes, while serum measurements demonstrated sustained therapeutic levels of functional alpha-1 antitrypsin protein. This represents the first reported case of successful hepatic gene correction for this condition with direct histological verification.
Why it matters
This case provides the first human tissue evidence that in vivo base editing can safely and effectively correct genetic mutations directly in the liver, potentially offering a curative treatment for alpha-1 antitrypsin deficiency and establishing proof-of-concept for treating other genetic liver diseases through direct gene correction rather than gene replacement.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background: Alpha-1 antitrypsin deficiency (AATD) caused by the PI*ZZ mutation (Glu342Lys) results in hepatic accumulation of misfolded AAT-Z protein and reduced circulating AAT levels, leading to progressive liver disease and emphysema. Gene correction therapy represents a potentially curative approach by directly correcting the underlying genetic defect. We report the first case of successful hepatic gene correction with early histological and functional assessment. Methods/Case presentation: We report the case of a 66-year-old male patient with PI*ZZ AATD who underwent gene correction therapy within the YOLT-202 phase I/Ia clinical trial (clinical trial.gov ID NCT07193615). Ten weeks post treatment a liver biopsy was performed to re-evaluate pre-existing F2 liver fibrosis as measured by elastography before entering the study. Serum samples allowed functional assessment of the AAT-mediated elastase inhibition. Results: Liver biopsy did not show signs of hepatic inflammation and demonstrated 54% (Sanger) and 57% (Illumina) gene correction rate of the PI*ZZ variant on the DNA level with no bystander edits or off-target effects. Following a transient elevation of transaminases during the early post-treatment period, liver enzymes normalized. Monthly serum AAT measurements demonstrated biologically active and stable therapeutic levels throughout follow-up. Conclusions: This case demonstrates efficient and precise hepatic gene correction without concerning histological alterations and with substantial improvement of functional parameters, supporting the feasibility and safety of gene editing approaches for AATD.