JBCGenetics |

Original Article

Volume: 2 | Issue: 1 | Published: Jan 01, 2019 | 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: Kimberly A. Coughlan , Rajanikanth J. Magant , Andrea Frassetto , Christine M. DeAntonis , Meredith Wolfrom , Anne-Renee Graham , Shawn M. Hillier , Steven Fortucc , HoorAl Jandal , Sue-Jean Hong , Paloma H. Giangrande , Paolo G. V. Martin

Article Info

Authors

Kimberly A. Coughlan

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Rajanikanth J. Magant

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Andrea Frassetto

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Christine M. DeAntonis

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Meredith Wolfrom

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Anne-Renee Graham

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Shawn M. Hillier

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Steven Fortucc

Rare Diseases, Moderna Inc, Cambridge, MA, USA

HoorAl Jandal

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Sue-Jean Hong

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Paloma H. Giangrande

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Paolo G. V. Martin

Rare Diseases, Moderna Inc, Cambridge, MA, USA

Publication History

Received: November 13, 2018

Accepted: December 05, 2018

Published: January 01, 2019

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

Pubmed Style

Kimberly A. Coughlan, Rajanikanth J. Magant, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucc, HoorAl Jandal, Sue-Jean Hong, Paloma H. Giangrande, Paolo G. V. Martin. Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBC Genetics. 2019; 01 (January 2019): 28-39. doi:10.24911/JBCGenetics/183-1542047633

Web Style

Kimberly A. Coughlan, Rajanikanth J. Magant, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucc, HoorAl Jandal, Sue-Jean Hong, Paloma H. Giangrande, Paolo G. V. Martin. Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. https://jbcgenetics.com/articles/2168 [Access: June 27, 2025]. doi:10.24911/JBCGenetics/183-1542047633

AMA (American Medical Association) Style

Vancouver/ICMJE Style

Kimberly A. Coughlan, Rajanikanth J. Magant, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucc, HoorAl Jandal, Sue-Jean Hong, Paloma H. Giangrande, Paolo G. V. Martin. Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBC Genetics. (2019), [cited June 27, 2025]; 01 (January 2019): 28-39. doi:10.24911/JBCGenetics/183-1542047633

Harvard Style

Kimberly A. Coughlan, Rajanikanth J. Magant, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucc, HoorAl Jandal, Sue-Jean Hong, Paloma H. Giangrande, Paolo G. V. Martin (2019) Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBC Genetics, 01 (January 2019): 28-39. doi:10.24911/JBCGenetics/183-1542047633

Chicago Style

Kimberly A. Coughlan, Rajanikanth J. Magant, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucc, HoorAl Jandal, Sue-Jean Hong, Paloma H. Giangrande, Paolo G. V. Martin. "Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing." 01 (2019), 28-39. doi:10.24911/JBCGenetics/183-1542047633

MLA (The Modern Language Association) Style

Kimberly A. Coughlan, Rajanikanth J. Magant, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucc, HoorAl Jandal, Sue-Jean Hong, Paloma H. Giangrande, Paolo G. V. Martin. "Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing." 01.January 2019 (2019), 28-39. Print. doi:10.24911/JBCGenetics/183-1542047633

APA (American Psychological Association) Style

Kimberly A. Coughlan, Rajanikanth J. Magant, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucc, HoorAl Jandal, Sue-Jean Hong, Paloma H. Giangrande, Paolo G. V. Martin (2019) Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. , 01 (January 2019), 28-39. doi:10.24911/JBCGenetics/183-1542047633