Korro Bio reports preclinical data for KRRO-111 targeting AATD

Preclinical results for KRRO-111 indicate the RNA editing therapeutic achieved significant editing of the SERPINA1 gene in mouse models, suggesting potential to address both lung and liver manifestations of alpha-1 antitrypsin deficiency (AATD) through a subcutaneous delivery method. Korro Bio, Inc. (Nasdaq: KRRO) announced the data, highlighting the compound’s differentiated approach to treating the genetic disorder.

The company stated that KRRO-111 is a proprietary GalNAc-conjugated RNA-editing oligonucleotide designed to be taken up by liver cells. Once inside, it utilizes endogenous Adenosine Deaminase Acting on RNA (ADAR) enzymes to correct pathogenic SERPINA1 transcripts. This mechanism aims to enable the production of functional M-AAT while reducing the synthesis of mutant Z-AAT, which is associated with liver injury.

In repeat-dose studies using NSG-PiZ mice, KRRO-111 produced SERPINA1 mRNA editing levels of 96%. M-AAT comprised 93% of total circulating AAT, with total AAT concentrations reaching 172 μM at Day 57, a level the company noted was approximately six times higher than vehicle controls. In immunocompetent C57BL/6-PiZ mice, the treatment reduced whole liver Z-AAT levels by 95% relative to vehicle controls, as measured by liquid chromatography tandem mass spectrometry at Day 57.

Single-dose studies in C57BL/6-PiZ mice showed up to 91% SERPINA1 editing, with M-AAT accounting for up to 88% of total circulating AAT. Both responses remained detectable through at least Day 42 post-dose. The compound exhibited potent RNA editing activity with an EC50 of approximately 1 nM, achieving up to 98% editing in mouse and human hepatocytes.

Loïc Vincent, PhD, Chief Scientific Officer of Korro, stated that KRRO-111 restored functional M-AAT while reducing toxic Z-AAT. He described the dual profile and redosable subcutaneous presentation as necessary for a next-generation AATD therapy. Ram Aiyar, PhD, MBA, Chief Executive Officer and President of Korro, noted that current augmentation therapy addresses only part of the disease burden and that no approved therapy exists for the liver disease component.

The company expects to submit regulatory filings for KRRO-111 in the first half of 2027. AATD is a genetic disorder most commonly caused by a missense mutation in the SERPINA1 gene, affecting an estimated 3.4 million individuals worldwide. The only current FDA-approved treatment is augmentation therapy, a once-weekly infusion of pooled human plasma-derived AAT protein.