Wave Life Sciences Ltd. (NASDAQ:WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced the first proof-of-concept preclinical data for its ADAR (adenosine deaminases acting on RNA)-mediated RNA editing (“ADAR editing”) program in alpha-1 antitrypsin deficiency (AATD). Up to 40 percent editing of human SERPINA1 Z-allele mRNA in the liver was observed at a single timepoint, which resulted in a therapeutically meaningful increase in circulating functional wild-type AAT protein. This initial in vivo study utilized Wave’s proprietary transgenic mouse model, which has both the human SERPINA1 Z-allele as well as human ADAR that is expressed comparably to human cells.
“These findings are a critical contribution to the genetic medicines field, as they represent the first proof-of-concept in vivo data for RNA editing using endogenous ADAR enzymes in AATD. They also reinforce Wave’s leadership position in the RNA editing field, as we continue to observe meaningful and significant levels of editing in animal models, including in mice and NHPs, which paves the way for translating this technology to the clinic,” said Paul Bolno, President and Chief Executive Officer of Wave Life Sciences. “Wave’s approach to RNA editing using endogenous ADAR and our AATD program have advanced quickly, with the team demonstrating immense creativity and tenacity to reach this important milestone. We look forward to presenting additional in vivo data in the second half of this year and continuing our progress towards the clinic.”
Wave’s AATD program, the first to utilize its ADAR editing modality, uses GalNAc-conjugated oligonucleotides to correct the single base mutation in mRNA derived from the SERPINA1 Z allele. ADAR editing provides a simple and efficient approach to treating AATD by simultaneously reducing aggregation of mutated, misfolded alpha-1 antitrypsin protein (Z-AAT) and increasing circulating levels of wild-type protein (M-AAT), thus having the potential to address both the lung and liver manifestations of the disease while avoiding risk from permanent off-target changes to the DNA. Wave is initially focusing on homozygous “ZZ” patients who have the highest risk of disease and where RNA editing may result in a heterozygous “MZ” phenotype, which would result in a substantially lower risk of disease.
