| First Author | Martinez-Turrillas R | Year | 2022 |
| Journal | Mol Ther Methods Clin Dev | Volume | 25 |
| Pages | 137-146 | PubMed ID | 35402636 |
| Mgi Jnum | J:327319 | Mgi Id | MGI:7329860 |
| Doi | 10.1016/j.omtm.2022.03.006 | Citation | Martinez-Turrillas R, et al. (2022) In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria. Mol Ther Methods Clin Dev 25:137-146 |
| abstractText | 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. |
