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  • Title: CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I.
    Author: Zabaleta N, Barberia M, Martin-Higueras C, Zapata-Linares N, Betancor I, Rodriguez S, Martinez-Turrillas R, Torella L, Vales A, Olagüe C, Vilas-Zornoza A, Castro-Labrador L, Lara-Astiaso D, Prosper F, Salido E, Gonzalez-Aseguinolaza G, Rodriguez-Madoz JR.
    Journal: Nat Commun; 2018 Dec 21; 9(1):5454. PubMed ID: 30575740.
    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.
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