LNP-mediated in vivo base editing corrects Agxt to cure primary hyperoxaluria type 1

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder caused by AGXT mutations, leading to hepatic oxalate overproduction, nephrolithiasis, and progressive renal failure. This study aims to evaluate the therapeutic potential of base editors delivered via lipid nanoparticles (LNPs) for treating PH1.

We utilized LNPs to deliver the base editor variant spG-ABE8e into a PH1 rat model. A single-dose injection of LNP-ABE was administered to assess its efficacy in correcting the pathogenic Agxt point mutation.

Treatment with LNP-ABE achieved highly efficient correction of the Agxt mutation, which resulted in the normalization of urinary oxalate excretion, prevention of calcium oxalate deposits, and reversal of renal injury-associated gene expression profiles in PH1 rats. Furthermore, this study identified the minimum Agxt correction efficiency required for urinary oxalate normalization.

Our findings demonstrate that LNP-mediated delivery of base editors can effectively correct AGXT pathogenic mutations and ameliorate disease phenotypes in PH1, providing critical preclinical benchmarks for future clinical translation.

The base editor precisely corrected the Agxt gene with high efficiency in PH1 rats. LNP-delivered Adenine Base Editor (ABE) normalized urinary oxalate levels and prevented calculus formation. This study identified the minimal Agxt correction efficiency required for urinary oxalate normalization.