Liver biopsy ten weeks after a single gene therapy infusion showed correction of the faulty DNA “letter” in 54–57% of gene copies in a patient with alpha-1 antitrypsin deficiency, with no unintended edits detected

Liver biopsy ten weeks after a single gene therapy infusion showed correction of the faulty DNA “letter” in 54–57% of gene copies in a patient with alpha-1 antitrypsin deficiency, with no unintended edits detected

A 66-year-old man with a mutation in both copies of the gene received YOLT-202, a treatment that changes one DNA letter in liver cells. On November 2, the European Association for the Study of the Liver announced the report in the Journal of Hepatology. The authors include physicians at Hannover Medical School and employees of YolTech, the treatment’s developer. They describe this as the first case in which this type of liver editing was assessed directly by biopsy.

Alpha-1 antitrypsin deficiency is caused by an error in one “letter” of the gene that the liver uses to make this protein. The faulty protein clumps together inside liver cells, damaging the liver, and only small amounts reach the blood. The normal protein inhibits elastase, an enzyme released by immune cells that breaks down lung tissue. Without this protection, emphysema develops. Weekly infusions of the protein from donor plasma protect the lungs. According to the press release, transplantation is the only definitive treatment for the liver disease.

The authors’ approach is to correct the gene itself so that the liver stops producing the toxic protein and resumes producing the normal protein. In the patient’s gene, the letter G (guanine) has been replaced by A (adenine). YOLT-202 is a base editor packaged in lipid nanoparticles that deliver it to the liver. It changes A back to G while leaving the DNA double helix intact. The authors say this may reduce the risk of unintended DNA insertions and deletions. The patient received a single infusion of 35 mg, the lowest planned dose.

In September, competing developer Beam Therapeutics reported blood test results after a 60 mg dose of its editor BEAM-302: normal protein accounted for 93% of total alpha-1 antitrypsin. Direct assessment of how many gene copies have been corrected and whether unintended edits have occurred (changes to other “letters” near the target or elsewhere in the genome) requires tissue DNA. The biopsy was performed outside the trial protocol because liver stiffness measured before treatment was elevated, a sign of possible fibrosis, or scar tissue buildup.

The tissue DNA was sequenced using two methods. Sanger sequencing, which reads the region of the gene surrounding the mutation, showed correction in 54% of gene copies; whole-genome sequencing showed 57%. Nearby adenines that the editor might also have changed remained unchanged. No unintended substitutions were detected at sites where editing errors had been found in preclinical experiments. The press release compares this result with carrier status: people with one faulty copy of the gene usually do not develop severe disease.

“We were genuinely surprised by the high correction efficiency and remarkable precision at such a low dose,” said Simon Krooss, the paper’s first author.

On day three after the infusion, ALT, an enzyme used as a marker of liver injury, reached 1,35 times the upper limit of normal and returned to normal by day 14. Liver sections showed no significant treatment-related inflammation, and clumps of faulty protein were visible in only a few cells. Previous studies have shown substantial accumulation in patients with this condition. By week ten, blood alpha-1 antitrypsin had risen from 0,15 to 0,7 g/l and remained above 0,57 g/l, the target threshold for donor protein infusions, throughout follow-up. In a laboratory assay, the patient’s protein inhibited elastase to a similar extent as normal protein.

By September, four patients had received the treatment, according to YolTech. In June, Serapha Bio licensed the treatment and agreed to go public on Nasdaq through a merger with Boundless Bio and raise approximately $230 million.