Development of ABO-101, a Novel Gene Editing Therapy for Primary Hyperoxaluria Type 1

Background: Primary Hyperoxaluria, or PH, is a group of rare genetic metabolic disorders characterized by the overproduction of oxalate by the liver. Oxalate builds up and accumulates in the kidneys and other organ systems, causing kidney damage and progression towards renal failure. PH1, the most common and clinically severe subtype of PH, results from a mutation of the AGXT gene which is expressed primarily in the liver. Here we present pre-clinical in vivo evidence supporting ABO-101 as a novel CRISPR-Cas-mediated gene editing therapy for the treatment of PH1. The current standard of care siRNA therapy for PH1 requires lifelong treatment and targets HAO1, which encodes the glycolate oxidase enzyme (GO) and is upstream of the mutant AGXT. Inhibition of HAO1 lowers the availability of oxalate precursors and thus results in a therapeutically meaningful reduction of oxalate levels and a corresponding increase in serum glycolate, a metabolic byproduct of HAO1 inhibition. Methods: ABO-101 was designed to specifically inactivate the HAO1 gene in liver hepatocytes and provide a durable reduction of oxalate levels through a single course of treatment. ABO-101 is comprised of a lipid nanoparticle (LNP) which encapsulates our proprietary engineered variant of Cas12i2 (ABR-001) and a guide RNA (gRNA), selected to share 100% sequence complementarity to the cynomolgus macaque NHP HAO1 gene. Results: In NHPs treated with ABO-101, we achieved HAO1 editing of approximately 60% in whole liver tissue, which correlates to a greater than 2x increase in serum glycolate, all with a well-tolerated safety profile. We also observed a dose-dependent increase in editing levels with a concomitant increase in serum glycolate levels and reduction of GO enzyme activity levels. In addition to both rodent and primate pharmacology data, we also describe our approach optimizing our lead gRNA, ratios of components inside the LNP, and the mRNA encoding the gene editing machinery; these optimizations resulted in our lead therapeutic candidate ABO-101. Conclusion: Taken together, these results provide in vivo proof of pharmacology for a gene editing approach and support further advancement of ABO-101 towards the clinic as a potential treatment for PH1.