Scientific publications

CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I

Dec 21, 2018 | Magazine: Nature Communications

Nerea Zabaleta, Miren Barberia, Cristina Martin-Higueras, Natalia Zapata-Linares, Isabel Betancor, Saray Rodriguez, Rebeca Martinez-Turrillas, Laura Torella, Africa Vales, Cristina Olagüe, Amaia Vilas-Zornoza, Laura Castro-Labrador, David Lara-Astiaso, Felipe Prosper, Eduardo Salido, Gloria Gonzalez-Aseguinolaza, Juan R Rodriguez-Madoz


Abstract

CRISPR/Cas9 technology offers novel approaches for the development of new therapies for many unmet clinical needs, including a significant number of inherited monogenic diseases. However, in vivo correction of disease-causing genes is still inefficient, especially for those diseases without selective advantage for corrected cells. We reasoned that substrate reduction therapies (SRT) targeting non-essential enzymes could provide an attractive alternative.

Here we evaluate the therapeutic efficacy of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I (PH1), a rare inborn dysfunction in glyoxylate metabolism that results in excessive hepatic oxalate production causing end-stage renal disease. A single systemic administration of an AAV8-CRISPR/Cas9 vector targeting glycolate oxidase, prevents oxalate overproduction and kidney damage, with no signs of toxicity in Agxt1-/- mice.

Our results reveal that CRISPR/Cas9-mediated SRT represents a promising therapeutic option for PH1 that can be potentially applied to other metabolic diseases caused by the accumulation of toxic metabolites.

CITATION  Nat Commun. 2018 Dec 21;9(1):5454. doi: 10.1038/s41467-018-07827-1.