2. Academic Validation
  3. Efficient and safe in vivo treatment of primary hyperoxaluria type 1 via LNP-CRISPR-Cas9-mediated glycolate oxidase disruption

Efficient and safe in vivo treatment of primary hyperoxaluria type 1 via LNP-CRISPR-Cas9-mediated glycolate oxidase disruption

  • Mol Ther. 2024 Oct 9:S1525-0016(24)00663-4. doi: 10.1016/j.ymthe.2024.10.003.
Yanhong Jiang 1,  Shuanghong Chen 1,  Shenlin Hsiao 1,  Haokun Zhang 2,  Da Xie 2,  Zi Jun Wang 2,  Wendan Ren 2,  Mingyao Liu 3,  Jiaoyang Liao 4,  Yuxuan Wu 5
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 200241, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 2 YolTech Therapeutics, Shanghai 201109, China.
  • 3 Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 200241, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. Electronic address: myliu@bio.ecnu.edu.cn.
  • 4 Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 200241, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. Electronic address: jyliao@bio.ecnu.edu.cn.
  • 5 Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 200241, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; YolTech Therapeutics, Shanghai 201109, China. Electronic address: yxwu@bio.ecnu.edu.cn.
PMID: 39385468 DOI: 10.1016/j.ymthe.2024.10.003
Abstract

Primary hyperoxaluria type 1 (PH1) is a severe genetic metabolic disorder caused by mutations in the AGXT gene, leading to defects in Enzymes crucial for glyoxylate metabolism. PH1 is characterized by severe, potentially life-threatening manifestations due to excessive oxalate accumulation, which leads to calcium oxalate crystal deposits in the kidneys and, ultimately, renal failure and systemic oxalosis. Existing substrate reduction therapies, such as inhibition of liver-specific glycolate oxidase (GO) encoded by HAO1 using siRNA or CRISPR-Cas9 delivered by adeno-associated virus, either require repeated dosing or have raised safety concerns. To address these limitations, our study employed lipid nanoparticles (LNPs) for CRISPR-Cas9 delivery to rapidly generate a PH1 mouse model and validate the therapeutic efficacy of LNP-CRISPR-Cas9 targeting the Hao1 gene. The LNP-CRISPR-Cas9 system exhibited efficient editing of the Hao1 gene, significantly reducing GO expression and lowering urinary oxalate levels in treated PH1 mice. Notably, these effects persisted for 12 months with no significant off-target effects, liver-induced toxicity, or substantial immune responses, highlighting the approach's safety and specificity. Furthermore, the developed humanized mouse model validated the efficacy of our therapeutic strategy. These findings support LNP-CRISPR-Cas9 targeting HAO1 as a promising and safer alternative for PH1 treatment with a single administration.

Keywords

CRISPR/Cas9; LNPs; PH1; PH1 treatment; genome editing; glycolate oxidase; lipid nanoparticles; primary hyperoxaluria type 1; urine oxalate.

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