The first clinical results for an RNA-editing oligonucleotide designed to correct a disease-causing single-base mutation in mRNA have been released. The company, Wave Life Sciences, says the agent WVE-006 restored more than 60% of wild-type functional protein in two individuals with the genetic disorder alpha-1 antitrypsin (ATT; encoded by SERPINA1) deficiency. ATT deficiency affects the liver owing to hepatic build-up of misfolded ATT protein, and causes lung disease owing to a lack of circulating ATT protein to protect the lungs from inflammatory damage. The RNA editor, potentially a first-in-class agent, acts by correcting a G-to-A mutation in the SERPINA1 Z allele transcript. Fifteen days after one dose, the patients’ functional AAT protein was almost seven micromolar, a level associated with a low risk of liver and lung disorders. AAT protein levels remained increased for two months in the patients.

“The level of mRNA editing … exceeded our expectations, and we expect [functional] AAT levels to continue to increase with repeat dosing,” said Wave’s president in the press release announcing the results. WVE-006 induces site-specific A-to-I changes in mRNA transcripts. Because the cell’s translation machinery reads I as G, ADAR editors correct pathogenic G-to-A mutations. WVE-006 is conjugated with N-acetylgalactosamine to facilitate hepatic delivery and phosphoryl guanidine backbone modifications improve efficiency. It is injected subcutaneously and does not use lipid nanoparticles for delivery. The molecule was part of a 2022 deal (worth $170 million upfront) with GSK, based in London, who will take over its development after the current trial has completed.