Original Article
JBCGenetics. 2019; 2(1): 28-39

Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing

Authors: Kimberly A. Coughlan, Rajanikanth J. Maganti, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucci, Hoor Al Jandal, Sue-Jean Hong, Paloma H. Giangrande, Paolo G.V. Martini.

View PDF HTML Fulltext DOI: 10.24911/JBCGenetics/183-1542047633

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


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Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing


Authors
Kimberly A Coughlan
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Rajanikanth J Maganti
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Andrea Frassetto
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Christine M DeAntonis
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Meredith Wolfrom
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Anne-Renee Graham
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Shawn M Hillier
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Steven Fortucci
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Hoor Al Jandal
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Sue-Jean Hong
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Paloma H Giangrande
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles

Paolo G V Martini
Rare Diseases, Moderna Inc, Cambridge, MA, USA
PubMed articlesGoogle scholar articles


Correspondence to:
. Paolo G.V. Martini, Rare Diseases, Moderna Inc, Cambridge, MA, USA;; paolo.martini@modernatx.com

Publication history
Received 13 Nov 2018
Revised 26 Apr 2019
Accepted 05 May 2019
Published online 23 May 2019
Published in print 16 Jun 2019

How to cite this article

Pubmed Style

Coughlan KA, Maganti RJ, Frassetto A, DeAntonis CM, Wolfrom M, Graham A, Hillier SM, Fortucci S, Jandal HA, Hong S, Giangrande PH, Martini PG. Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBCGenetics. 2019; 2(1): 28-39. doi:10.24911/JBCGenetics/183-1542047633


Web Style

Coughlan KA, Maganti RJ, Frassetto A, DeAntonis CM, Wolfrom M, Graham A, Hillier SM, Fortucci S, Jandal HA, Hong S, Giangrande PH, Martini PG. Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. https://www.jbcgenetics.com//?mno=16869 [Access: September 17, 2019]. doi:10.24911/JBCGenetics/183-1542047633


AMA (American Medical Association) Style

Coughlan KA, Maganti RJ, Frassetto A, DeAntonis CM, Wolfrom M, Graham A, Hillier SM, Fortucci S, Jandal HA, Hong S, Giangrande PH, Martini PG. Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBCGenetics. 2019; 2(1): 28-39. doi:10.24911/JBCGenetics/183-1542047633


Vancouver/ICMJE Style

Coughlan KA, Maganti RJ, Frassetto A, DeAntonis CM, Wolfrom M, Graham A, Hillier SM, Fortucci S, Jandal HA, Hong S, Giangrande PH, Martini PG. Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBCGenetics. (2019), [cited September 17, 2019]; 2(1): 28-39. doi:10.24911/JBCGenetics/183-1542047633


Harvard Style

Coughlan, K. A., Maganti, . R. J., Frassetto, . A., DeAntonis, . C. M., Wolfrom, . M., Graham, . A., Hillier, . S. M., Fortucci, . S., Jandal, . H. A., Hong, . S., Giangrande, . P. H. & Martini, . P. G. (2019) Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBCGenetics, 2 (1), 28-39. doi:10.24911/JBCGenetics/183-1542047633


Turabian Style

Coughlan, Kimberly A., Rajanikanth J. Maganti, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucci, Hoor Al Jandal, Sue-Jean Hong, Paloma H. Giangrande, and Paolo G.V. Martini. 2019. Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. Journal of Biochemical and Clinical Genetics, 2 (1), 28-39. doi:10.24911/JBCGenetics/183-1542047633


Chicago Style

Coughlan, Kimberly A., Rajanikanth J. Maganti, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucci, Hoor Al Jandal, Sue-Jean Hong, Paloma H. Giangrande, and Paolo G.V. Martini. "Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing." Journal of Biochemical and Clinical Genetics 2 (2019), 28-39. doi:10.24911/JBCGenetics/183-1542047633


MLA (The Modern Language Association) Style

Coughlan, Kimberly A., Rajanikanth J. Maganti, Andrea Frassetto, Christine M. DeAntonis, Meredith Wolfrom, Anne-Renee Graham, Shawn M. Hillier, Steven Fortucci, Hoor Al Jandal, Sue-Jean Hong, Paloma H. Giangrande, and Paolo G.V. Martini. "Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing." Journal of Biochemical and Clinical Genetics 2.1 (2019), 28-39. Print. doi:10.24911/JBCGenetics/183-1542047633


APA (American Psychological Association) Style

Coughlan, K. A., Maganti, . R. J., Frassetto, . A., DeAntonis, . C. M., Wolfrom, . M., Graham, . A., Hillier, . S. M., Fortucci, . S., Jandal, . H. A., Hong, . S., Giangrande, . P. H. & Martini, . P. G. (2019) Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. Journal of Biochemical and Clinical Genetics, 2 (1), 28-39. doi:10.24911/JBCGenetics/183-1542047633


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