Researchers have demonstrated successful correction of a disease-causing genetic mutation in the liver of a patient with alpha-1 antitrypsin deficiency (AATD), providing encouraging evidence for the potential of in vivo base editing to treat inherited liver and lung diseases. Published in the Journal of Hepatology, thestudy reports the first direct assessment of hepatic gene correction following lipid nanoparticle (LNP)-delivered base editing in a patient with AATD. The findings showed that more than half of the targeted gene copies had been successfully corrected, without detectable unintended editing.
AATD is caused by mutations in the SERPINA1 gene, which produces alpha-1 antitrypsin (AAT), a protein that protects lung tissue from enzyme-mediated damage. Patients with the severe Pi*ZZ genotype produce misfolded AAT that accumulates in the liver, potentially causing fibrosis and cirrhosis, while insufficient circulating AAT increases the risk of emphysema. Current treatments primarily focus on restoring circulating AAT levels rather than correcting the underlying genetic defect.
Led by researchers from Hannover Medical School and collaborating institutions in China, the study examined a 66-year-old male patient with Pi*ZZ AATD who received YOLT-202, an investigational adenine base-editing therapy developed by YolTech Therapeutics. Administered intravenously as part of an early-phase clinical trial, YOLT-202 uses LNPs to deliver editing machinery designed to correct the pathogenic SERPINA1 variant without introducing double-strand DNA breaks.
Ten weeks after a single 35 mg infusion, researchers performed a liver biopsy to investigate editing efficiency, potential unintended genetic changes, and tissue health. The biopsy revealed correction of the pathogenic SERPINA1 variant in 54 percent of alleles using Sanger sequencing and 57 percent using Illumina sequencing. Importantly, neither analysis identified unintended changes at nearby DNA positions, while examination of predicted off-target sites found no detectable unwanted editing. Histological assessment revealed only mild portal inflammation and fibrosis, with residual misfolded AAT aggregates detected in relatively few hepatocytes. No significant active liver injury was observed.
The treatment also produced sustained improvements in circulating AAT levels, rising from 0.15 g/L before treatment to 0.7 g/L at 10 weeks, exceeding the commonly used therapeutic threshold of 0.57 g/L. Functional testing confirmed that the circulating protein retained its ability to inhibit elastase. Although transient elevations in liver enzymes occurred shortly after infusion, levels normalized within two weeks.
The results provide some early clinical evidence that LNP-mediated base editing can achieve substantial genetic correction alongside sustained production of functional AAT. Larger clinical studies and longer follow-up will now be necessary to establish whether these molecular improvements translate into lasting protection against liver and lung disease.
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