Shanghai-based YolTech Therapeutics has announced the dosing of the first two patients in an Investigator-Initiated Trial (IIT) of YOLT-203, a pioneering in vivo CRISPR gene-editing therapy designed as a one-time curative treatment for primary hyperoxaluria type 1 (PH1). This early-phase trial marks a significant step forward in the application of in vivo gene editing for inherited metabolic disorders.
PH1 is a rare genetic disorder characterized by the excessive production and accumulation of oxalate in the kidneys and other organs. The condition typically manifests in childhood, often leading to kidney failure and the need for intensive hemodialysis, potentially followed by dual liver/kidney transplantation. Affecting an estimated 1-3 individuals per 1,000,000 in the general population, PH1 arises from mutations in the AGXT gene.
Targeting the Root Cause of PH1 with YOLT-203
YOLT-203 leverages YolTech's proprietary YolCas12 system to directly address the genetic mutations underlying PH1. The therapeutic candidate consists of the YolCas12 nuclease and a target-specific guide RNA, delivered via lipid nanoparticles (LNPs) to the liver. Once inside liver cells, YolCas12 aims to correct mutations in the AGXT gene, thereby reducing the production of oxalate and offering a potential curative treatment.
The intravenous administration of YOLT-203 allows for targeted delivery to liver cells, where the gene-editing process is intended to restore normal AGT enzyme function. The AGT enzyme, when functional, catalyzes the conversion of alanine and glyoxylate to pyruvate and glycine. In PH1, the deficiency of active AGT in the peroxisome leads to the oxidation of glyoxylate to oxalate in the cytosol, resulting in elevated oxalate levels in the blood and urine.
Promising Pre-clinical Data
Pre-clinical studies have demonstrated the high gene-editing activity of YolCas12 in both prokaryotic and eukaryotic cells. In vivo editing via LNP-mRNA delivery in mice and non-human primates also showed high efficiency, supporting the potential of YOLT-203 as a targeted gene-editing therapy.
Clinical Trial Details
The Phase 1 trial (NCT06511349), sponsored by RenJi Hospital in Shanghai, is designed to evaluate the safety and tolerability of YOLT-203 in Chinese individuals diagnosed with PH1. The trial also aims to preliminarily assess the impact of a single dose of YOLT-203 on plasma oxalate levels. The study plans to enroll a total of seven participants. The first adult participant was dosed on August 5, 2024, followed by the first child on August 20, 2024.
Currently, PH is incurable, and treatment strategies primarily focus on managing symptoms and preventing oxalate accumulation through high fluid intake and prescription siRNA-based medicines that indirectly reduce oxalate production. YOLT-203 represents a potentially transformative approach by directly targeting the genetic cause of the disease.
