Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-07827-1
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Funding
- ERA-NET E-Rare 3 research program JTC ERAdicatPH, Instituto de Salud Carlos III (ISCIII) [AC15/00036, PI16/00150]
- TERCEL (ISCIII) [RD16/0011/0005]
- MINECO [SAF2015-69796]
- Gobierno de Navarra [91/2016]
- Oxalosis & Hyperoxaluria Foundation
- Asociacion Amigos de la Universidad de Navarra (ADA)
- Fundacion para la Investigacion Medica Aplicada (FIMA)
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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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