YolTech Publish Breakthrough Research on Novel Gene-Editing Strategy for Treating Primary Hyperoxaluria Type 1 in Molecular Therapy

Shanghai, China— Primary Hyperoxaluria Type 1 (PH1) is a rare, inherited metabolic disorder caused by mutations in the Agxt gene, leading to an enzymatic deficiency in the liver. This deficiency results in the overproduction of oxalate, which combines with calcium in the kidneys to form calcium oxalate crystals. These crystals can cause nephrocalcinosis, progressive renal impairment, and, if left untreated, ultimately lead to end-stage renal disease (ESRD). Excessive oxalate can also deposit in multiple organs, leading to systemic damage and severe health risks.

Current treatments for PH1 involve inhibiting glycolate oxidase (GO)—a key enzyme upstream of AGT that catalyzes the conversion of glycolate to glyoxylate, a precursor of oxalate. While GO-targeting siRNA drugs are available in the clinic, they are associated with high costs and require frequent dosing, creating a substantial financial burden for patients.

In a groundbreaking development, YolTech’s founder Dr. Yuxuan Wu, in collaboration with researchers at East China Normal University, recently published an original research paper titled *Efficient and Safe In Vivo Treatment of Primary Hyperoxaluria Type 1 via LNP-CRISPR/Cas9-mediated Glycolate Oxidase Disruption* in *Molecular Therapy*. This study explores a novel in vivo gene-editing approach that uses lipid nanoparticles (LNPs) to deliver CRISPR/Cas9, effectively disrupting GO in a mouse model of PH1 and achieving a sustained reduction in oxalate levels.

To rapidly establish a PH1 mouse model, the research team delivered Cas9 mRNA and Agxt-targeting sgRNA via LNPs, adding 0.5% ethylene glycol (EG) to the animals' drinking water. The resulting model displayed elevated urinary oxalate levels and nephrocalcinosis, confirming the model's reliability. Subsequently, the team identified a highly efficient sgRNA targeting the mouse Hao1 gene and used LNPs to deliver Cas9 mRNA and Hao1-4 sgRNA via intravenous injection in the PH1 mice. Over a 12-month monitoring period, treated animals demonstrated stable gene-editing efficiency, significantly reduced oxalate levels, and no signs of nephrocalcinosis, suggesting that this strategy can effectively alleviate PH1 symptoms.

To comprehensively assess the safety of this gene-editing approach, researchers conducted detailed analyses of liver toxicity, immune response, and potential off-target effects. Results showed that editing activity was largely liver-specific, with minimal off-target effects. Additionally, no liver toxicity or immune reactions were observed, underscoring the safety profile of this approach and supporting its clinical application.

The study also evaluated humanized HAO1 gene mouse models, confirming effective in vivo editing and therapeutic outcomes in the humanized PH1 mouse model. This research represents a major step toward clinical application for PH1, where YolTech has initiated clinical trials with promising initial results.

Overall, the study introduces an innovative LNP-mediated in vivo gene-editing technique that demonstrates high efficacy and lasting therapeutic benefit from a single dose, offering a new avenue for treating PH1 and potentially improving patient quality of life. Furthermore, this breakthrough method sets a precedent for future gene therapies targeting related diseases.

Dr. Yuxuan Wu, YolTech’s founder; Dr. Jiaoyang Liao, Associate Researcher; and Professor Mingyao Liu from East China Normal University are co-corresponding authors of this publication. Doctoral candidates Yanhong Jiang and Shenglin Xiao, along with Associate Researcher Shuanghong Chen, are co-first authors. YolTech’s Co-founder, Dr. Zijun Wang, provided critical support for the research.

About YolTech

YolTech Therapeutics is a clinical-stage in vivo gene editing company committed to pioneering the next generation of precision genetic medicines. Our approach combines innovative gene editing technologies with an advanced lipid nanoparticle (LNP) delivery system, creating a versatile platform designed to address a wide range of serious diseases. Central to our mission is the development of internal capabilities, including end-to-end manufacturing, to ensure the highest standards of quality and scalability. Our lead candidate, targeting ATTR, marks a significant milestone as China’s first LNP-mediated in vivo gene editing therapy to enter clinical development. With promising early clinical outcomes, YolTech is also advancing therapies for familial hypercholesterolemia (FH) and primary hyperoxaluria type 1 (PH1). As a company dedicated to transforming the treatment landscape, YolTech continues to push the boundaries of what is possible in gene editing. For more information, please visit www.yoltx.com.