Adenosine deaminase acting on RNA 1–Serpin family A member 1 mRNA complex (ADAR1–SERPINA1 mRNA complex)

The ADAR1–SERPINA1 mRNA complex is a therapeutic target assembly formed by the recruitment of the endogenous enzyme Adenosine Deaminase Acting on RNA 1 (ADAR1; UniProt P55265) to the Serpin Family A Member 1 (SERPINA1; UniProt P01009) messenger RNA [1, 2]. This interaction is typically facilitated by engineered oligonucleotides, such as WVE-006, designed to correct the PiZ mutation (E342K), which is the primary cause of Alpha-1 antitrypsin deficiency (AATD) [3]. In this complex, ADAR1 performs a site-specific hydrolytic deamination of adenosine to inosine at the mutation site [4]. Since the ribosome interprets inosine as guanosine, the editing process restores the wild-type amino acid sequence during translation [4]. This dual-action mechanism increases the secretion of functional Alpha-1 antitrypsin to protect the lungs while simultaneously reducing the production of toxic, misfolded protein aggregates in the liver [3]. Current drug development focuses on using ADAR-mediated RNA editing (AIMers) to provide a durable, non-genomic correction of the underlying genetic defect [3, 4]. References: [1] UniProt P55265; [2] UniProt P01009; [3] Wave Life Sciences, 2024; [4] Monian et al., Nature Biotechnology, 2022; [5] Korro Bio, 2024.

Other names

ADAR1-A1AT mRNA complexADAR-mediated SERPINA1 RNA editing complexADAR1-SERPINA1 transcript complex

Recruitment of endogenous ADAR1 to SERPINA1 mRNA via an antisense oligonucleotide to catalyze site-specific adenosine-to-inosine (A-to-I) deamination, correcting the Z-mutation (E342K).