Preclinical evaluation of AGT mRNA replacement therapy for primary hyperoxaluria type I disease.

Abstract

Primary hyperoxaluria type 1 (PH1) is a rare inherited liver disorder caused by alanine glyoxylate aminotransferase (AGT) dysfunction, leading to accumulation of glyoxylate which is then converted into oxalate. Excessive oxalate results in kidney damage due to deposition of oxalate crystals. We have developed an mRNA-based protein replacement therapy for PH1 to restore normal glyoxylate to glycine metabolism. Sequence optimized humanmRNA (mRNA) was encapsulated in lipopolyplex (LPP) and produced functional AGT enzyme in peroxisomes. Pharmacokinetics and pharmacodynamics (PK/PD) were evaluated in vitro and in vivo. PK demonstrated thatmRNA and AGT protein maintained high expression levels for up to 48 hours. A single 2 mg/kg dose inQ84rats achieved a 70% reduction in urinary oxalate. Toxicological assessment identified the highest nonserious toxic dose (HNSTD) as 2 mg/kg. These findings affirm the efficacy and safety ofmRNA/LPP and support its clinical application in PH1 treatment.