Novel AAV843 Vector-Mediated Gene Replacement Therapy Rescues Primary Hyperoxaluria Type I in Mice.

Area of Science:

• Genetics and Molecular Biology
• Nephrology
• Gene Therapy

Background:

• Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder causing severe kidney damage due to oxalate deposition.
• Current treatments for PH1 are limited, highlighting the need for novel therapeutic strategies.
• Gene replacement therapy is a potential treatment for inherited metabolic disorders like PH1.

Purpose of the Study:

• To evaluate the efficacy and safety of AAV843-mediated gene replacement therapy for PH1.
• To establish a PH1 mouse model for testing gene therapy interventions.
• To assess the impact of gene therapy on oxalate levels, renal pathology, and related molecular pathways.

Main Methods:

• Characterization of a PH1 mouse model with complete loss of alanine-glyoxylate aminotransferase (AGT) expression.
• Induction of hyperoxaluria in PH1 mice via glyoxylic acid exposure.
• Delivery of human AGXT cDNA using the liver-tropic AAV843 vector.
• Assessment of urinary oxalate, hepatic AGT levels, renal histology, and molecular markers of inflammation and fibrosis.

Main Results:

• Gene therapy normalized urinary oxalate levels and restored hepatic AGT expression in PH1 mice.
• Significant reduction in renal calcium oxalate deposition, inflammation, necroptosis, and fibrosis was observed.
• AAV843 vector demonstrated liver-specific transgene expression without hepatotoxicity.

Conclusions:

• AAV843-mediated AGXT gene replacement is a safe and effective therapeutic strategy for PH1.
• This gene therapy approach achieves phenotypic correction in a preclinical PH1 model.
• Further preclinical studies are warranted to advance this promising treatment for PH1 patients.