ABO-101, a Novel Gene Editing Therapy for Primary Hyperoxaluria Type 1, Is Effective and Well Tolerated in Nonhuman Primates (NHPs) and Results in High-Fidelity Editing in Primary Hepatocytes

Background: Primary hyperoxaluria (PH) is a group of rare genetic metabolic disorders characterized by the overproduction of oxalate by the liver. PH1, the most common and clinically severe subtype of PH, results from a mutation of the AGXT gene. The current standard of care for PH1 is siRNA therapy that requires repeated lifelong treatments and targets HAO1, which encodes the glycolate oxidase enzyme (GO) and is upstream of the mutant AGXT. Methods: Here, we describe a gene editing approach targeting HAO1 to durably reduce the activity of GO enzyme after a single administration. We show that our gene editing therapeutic candidate, ABO-101, has demonstrated signals of efficacy and safety across multiple preclinical models, a critical step in moving this therapeutic candidate into clinical trials for PH1 patients. ABO-101 was designed to specifically inactivate HAO1 in hepatocytes and provide durable reduction of oxalate levels after a single course of treatment. Results: We demonstrate durable editing and long-lasting reduction of oxalate (>30% reduction) in the Agxt KO mouse model of PH1 after a single administration of mABO-101 out to 12 months post-dose. When administered to juvenile Agxt KO mice, reduction of oxalate is maintained into adulthood. Further, staggered dosing of mABO-101 before or after dosing of Hao1-targeting siRNA results in sustained reductions of urinary oxalate levels in Agxt KO mice, indicating the potential for ABO-101 to be administered before or after exposure to siRNA. In addition to mouse pharmacology, NHPs treated with ABO-101 achieved HAO1 editing of approximately 60% in whole liver tissue, which indicates editing of the majority of hepatocytes and drives >80% reduction of GO activity. Lastly, we highlight our genotoxicity and reproductive toxicity data packages demonstrating high fidelity of ABO-101 across >1,500 candidate off-target sites; the maintenance of the chromosomal structure; and lack of germline transmission in vivo. Conclusion: Taken together, these results demonstrate signals of efficacy in mice and NHPs and safety at the genome-wide and organismal level, further supporting the advancement of ABO-101 into the clinic as a potential treatment for PH1. Funding: Commercial Support - Arbor Biotechologies