Alpha-1 antitrypsin deficiency (AATD), one of the most common serious genetic diseases of the liver and lungs, affects an estimated 100,000 Americans with its most severe form — most of them carrying two copies of the PIZZ allele, a single-nucleotide substitution that causes misfolding and aggregation of the SERPINA1 protein in liver cells. A medRxiv preprint posted this week reports that a single patient in a Phase I/Ia trial received an intravenous infusion of an investigational base editor, YOLT-202, and ten weeks later underwent a liver biopsy. The histological result: 54% on-target correction of the PIZZ allele by Sanger sequencing and 57% by Illumina next-generation sequencing, with no off-target edits detected.
The case report, which has not yet been peer reviewed, is the first published histological evidence that base editing can correct a disease-causing point mutation at therapeutically relevant efficiency in a living human organ.
What base editing is — and why it matters
Unlike earlier CRISPR-Cas9 approaches, which create double-strand DNA breaks and rely on the cell’s repair machinery to introduce changes, base editors use a modified, nickase form of Cas9 paired with a deaminase enzyme to make precise single-nucleotide changes without breaking both strands of the DNA helix. The approach can convert an A to a G (adenine base editors, or ABEs) or a C to a T (cytosine base editors), making it well suited to correcting the class of point mutations responsible for many hereditary diseases — including the Glu342Lys (E342K) substitution that causes the PI*ZZ allele in SERPINA1.
YOLT-202 delivers its base-editing machinery as lipid nanoparticle-encapsulated mRNA directly to hepatocytes, the liver cells where SERPINA1 is expressed. The approach targets hepatocytes because they are both the site of the pathological protein aggregation that causes liver injury and the source of the circulating AAT protein that, when deficient, leads to pulmonary emphysema in AATD patients.
The biopsy
The biopsy was taken ten weeks after the patient received a single intravenous infusion under the Phase I/Ia dose-escalation trial (NCT07193615). Sequencing of biopsy-derived hepatocyte DNA showed correction of 54% of PI*ZZ alleles by Sanger sequencing and 57% by Illumina deep sequencing. Whole-genome sequencing and targeted amplicon sequencing at predicted off-target sites revealed no detectable off-target edits at the sensitivity levels tested.
The 54–57% correction figure represents on-target allele editing in sampled liver tissue. Whether that percentage translates to a proportional increase in circulating normal AAT protein — and whether such levels would be sufficient to prevent disease progression in lung or liver — will be assessed in subsequent cohorts.
Context and caveats
This is a single-patient case report from a Phase I/Ia trial designed primarily to assess safety and dosing. No safety findings are reported in the preprint beyond the biopsy sequencing data. As an unreviewed preprint, the findings should be interpreted with appropriate caution: this is an early signal, not a clinical result.
Even so, few gene-editing technologies have produced direct molecular confirmation of on-target correction in a human organ at this efficiency. Prior gene therapies for AATD, including gene-augmentation approaches that add a functional SERPINA1 copy without correcting the underlying mutation, have shown clinical benefit but do not eliminate the misfolded protein that accumulates in the liver and drives hepatotoxicity. A base-editing approach that corrects the mutation itself offers the theoretical advantage of restoring normal protein folding at the source.