Original Article
Volume: 2 | Issue: 1 | Published: Dec 05, 2018 | Pages: 28 - 39 | DOI: 10.24911/JBCGenetics/183-1542047633
Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing
Authors: Monika Maya Wahi , Monika Maya Wahi , Monika Maya Wahi , Monika Maya Wahi , Monika Maya Wahi , Monika Maya Wahi , Monika Maya Wahi , Monika Maya Wahi , HoorAl Jandal , HoorAl Jandal , HoorAl Jandal , HoorAl Jandal
Article Info
Authors
Monika Maya Wahi
Rare Diseases, Moderna Inc, Cambridge, MA, USA
Monika Maya Wahi
Rare Diseases, Moderna Inc, Cambridge, MA, USA
Monika Maya Wahi
Rare Diseases, Moderna Inc, Cambridge, MA, USA
Monika Maya Wahi
Rare Diseases, Moderna Inc, Cambridge, MA, USA
Monika Maya Wahi
Rare Diseases, Moderna Inc, Cambridge, MA, USA
Monika Maya Wahi
Rare Diseases, Moderna Inc, Cambridge, MA, USA
Monika Maya Wahi
Rare Diseases, Moderna Inc, Cambridge, MA, USA
Monika Maya Wahi
Rare Diseases, Moderna Inc, Cambridge, MA, USA
HoorAl Jandal
Rare Diseases, Moderna Inc, Cambridge, MA, USA
HoorAl Jandal
Rare Diseases, Moderna Inc, Cambridge, MA, USA
HoorAl Jandal
Rare Diseases, Moderna Inc, Cambridge, MA, USA
HoorAl Jandal
Rare Diseases, Moderna Inc, Cambridge, MA, USA
Publication History
Received: November 13, 2018
Accepted: May 05, 2019
Published: December 05, 2018
Abstract
Background: Primary Hyperoxaluria Type 1 (PH1) is an inborn error of metabolism caused by mutations in the AGXT gene, which encodes for the hepatocyte-specific enzyme alanine: glyoxylate aminotransferase (AGT). AGT catalyzes the conversion of glyoxylate to glycine in the peroxisome and prevents the build-up of oxalate which occurs in PH1. This causes nephrocalcinosis, systemic oxalosis, and end-stage renal disease. Liver transplant is currently the only curative treatment available. Although a mouse model has previously been generated, the severity of the reported disease phenotype varies, and a better understanding of the genotype-phenotype relationship in both the mouse model and human disease is needed. Methods: We developed an Agxt-/- mouse model using CRISPR/Cas9-mediated gene editing. We performed a natural history study and ethylene glycol (EG) challenge to evaluate the phenotype of this mouse. Results: Agxt-/- mice had elevated plasma glycolate, urine glycolate, and urine oxalate levels compared to Agxt+/+ mice. A small subset of Agxt-/- mice developed minimal nephrocalcinosis (1/8 at 12 weeks, 1/8 at 26 weeks, 0/8 at 39 weeks, and 3/7 at 52 weeks of age). When challenged with 0.7% or 1.2% EG in drinking water for 3 weeks, 2/10 Agxt-/- mice developed nephrocalcinosis. Agxt2mRNA and protein expression were unchanged between Agxt-/- and Agxt+/+ mice. Hydroxy acid oxidase 1(Hao1) messenger ribonucleic acid (mRNA) levels were unchanged, but the corresponding glycolate oxidase protein was increased in Agxt-/- mice. Conclusion: We have created an Agxt-/- mouse model which resembles much of the clinical phenotype of PH1 patients and will be a useful tool in developing novel therapies for this devastating disease.
Keywords: Primary Hyperoxaluria Type 1, CRISPR/Cas9, nephrocalcinosis, inborn error of metabolism
