CRISPR/Cas9-mediated GO disruption as treatment for primary hyperoxaluria type I

CRISPR/Cas9 technology offers novel approaches for the development of new therapies for many unmet clinical needs and, in particular, for 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. We evaluated 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 AAV-CRISPR/Cas9 vector targeting glycolate oxidase prevented 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, which are caused by the accumulation of toxic metabolites.