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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

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,R

doi

10.1038/s41467-018-07827-1

subject

Has Abstract

pub_date

2018-12-21 00:00:00

pages

5454

issue

1

issn

2041-1723

pii

10.1038/s41467-018-07827-1

journal_volume

9

pub_type

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