In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria

Genome-editing strategies, especially CRISPR-Cas9 systems, have substantially increased the efficiency of innovative therapeutic approaches for monogenic diseases such as primary hyperoxalurias (PHs). We have previously demonstrated that inhibition of glycolate oxidase using CRISPR-Cas9 systems represents a promising therapeutic option for PH type I (PH1). Here, we extended our work evaluating the efficacy of liver-specific inhibition of lactate dehydrogenase (LDH), a key enzyme responsible for converting glyoxylate to oxalate; this strategy would not be limited to PH1, being applicable to other PH subtypes. In this work, we demonstrate a liver-specific inhibition of LDH that resulted in a drastic reduction of LDH levels in the liver of PH1 and PH3 mice after a single-dose delivery of AAV8 vectors expressing the CRISPR-Cas9 system, resulting in reduced urine oxalate levels and kidney damage without signs of toxicity. Deep sequencing analysis revealed that this approach was safe and specific, with no off-targets detected in the liver of treated animals and no on-target/off-tissue events. Altogether, our data provide evidence that in vivo genome editing using CRISPR-Cas9 systems would represent a valuable tool for improved therapeutic approaches for PH.

Automated summary

This study demonstrates the efficacy of liver-specific inhibition of lactate dehydrogenase (LDH) using CRISPR-Cas9 systems for treating primary hyperoxalurias (PHs). The inhibition led to reduced levels of LDH in the liver, resulting in decreased urine oxalate levels and kidney damage without any signs of toxicity. The findings suggest that in vivo genome editing with CRISPR-Cas9 systems could be a valuable tool for improving therapeutic approaches for PH.