Primary hyperoxaluria type 1 (PH1) is a rare metabolic disease characterized by oxalate overproduction in the liver and its toxic accumulation in the kidneys. CRISPR/Cas9 targeting the Hao1 gene resulted in effective substrate reduction in a preclinical model of PH1. However, the possibility of off-target modification remains a safety concern. Here, we investigate the use of CRISPR/CasRx, a programmable RNA editor that allows targeted gene knockdown without modifying the DNA. First, we chose the most effective gRNAs targeting Hao1 mRNA in transfected mammalian cells. Bystander cleavage of exogenous non-targeted mRNAs was detected, as evidenced by a considerable drop in reporter protein (GFP) expression, whereas endogenous housekeeping protein remained unaffected. We assembled the gRNAs with lower bystander effect in an array construction and controlled CasRx expression by a liver-specific promoter. Then, we evaluated their efficacy in vitro, revealing a substantial decrease in GO protein expression. These encouraging findings supported the in vivo evaluation of CasRx.  AAV8 vectors delivering CasRx in combination with single or multiple gRNAs were designed, and tested in mice. The animals were simultaneously injected with AAV8-Luciferase to test the bystander activity in vivo. The reduction in Luciferase and CasRx confirmed the trans cleavage of exogenously expressed genes, which was substantially higher in animals treated with multiple gRNAs. However, GO protein levels were not reduced, although the collateral effect suggested otherwise. In summary, our in vivo data does not support the use of CasRx as an alternate substrate reduction therapy for the treatment of PH1.