Lipid nanoparticle-mediated base-editing of the Hao1 gene achieves sustainable primary hyperoxaluria type 1 therapy in rats.

Primary hyperoxaluria type 1 (PH1) is a severe hereditary disease, leading to the accumulation of oxalate in multiple organs, particularly the kidney. Hydroxyacid oxidase 1 (HAO1), a pivotal gene involved in oxalate production, is an approved target for the treatment of PH1. In this study, we demonstrated the discovery of several novel therapeutic sites of the Hao1 gene and the efficient editing of Hao1 c.290-2 A in vivo with lipid nanoparticles (LNP) delivered adenine base editing (ABE) mRNA. A single infusion of LNP-ABE resulted in a near-complete knockout of Hao1 in the liver, leading to the sustainable normalization of urinary oxalate (for at least 6 months) and complete rescue of the patho-physiology in PH1 rats. Additionally, a significant correlation between Hao1 editing efficiency and urinary oxalate levels was observed and over 60% Hao1 editing efficiency was required to achieve the normalization of urinary oxalate in PH1 rats. These findings suggest that the LNP-mediated base-editing of Hao1 c.290-2 A is an efficient and safe approach to PH1 therapy, highlighting its potential utility in clinical settings.