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

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 () and Juan R. Rodriguez-Madoz ()
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Nerea Zabaleta: University of Navarra, IdiSNA
Miren Barberia: University of Navarra, IdiSNA
Cristina Martin-Higueras: Universidad La Laguna, CIBERER
Natalia Zapata-Linares: University of Navarra, IdiSNA
Isabel Betancor: Universidad La Laguna, CIBERER
Saray Rodriguez: University of Navarra, IdiSNA
Rebeca Martinez-Turrillas: University of Navarra, IdiSNA
Laura Torella: University of Navarra, IdiSNA
Africa Vales: University of Navarra, IdiSNA
Cristina Olagüe: University of Navarra, IdiSNA
Amaia Vilas-Zornoza: University of Navarra, IdiSNA
Laura Castro-Labrador: University of Navarra, IdiSNA
David Lara-Astiaso: University of Navarra, IdiSNA
Felipe Prosper: University of Navarra, IdiSNA
Eduardo Salido: Universidad La Laguna, CIBERER
Gloria Gonzalez-Aseguinolaza: University of Navarra, IdiSNA
Juan R. Rodriguez-Madoz: University of Navarra, IdiSNA

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07827-1

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