First-in-human clinical study of an embryonic stem cell product for urea cycle disorders

Abstract

Abstract Background This study assesses the safety and efficacy of hepatocyte-like cell (HLC) infusion therapy derived from human embryonic stem cells as bridging therapy for neonatal-onset urea cycle disorders (UCD). The research includes both preclinical and clinical evaluations to determine the feasibility of HLC infusion as a therapeutic option for safer pediatric liver transplantation. Methods Preclinical studies were conducted to validate the safety, biodistribution, and ammonia metabolism capabilities of HLCs using SCID mice models of UCD and extensive animal studies. In the clinical trial, five neonates with UCD received HLC infusions, intending to maintain metabolic stability and exceed a target weight of over 6 kg, which is considered necessary for safer liver transplantation. Results Preclinical studies demonstrated that HLCs successfully engrafted in the liver without adverse migration or tumor formation and effectively elongated survival. Clinically, all five neonates exceeded the target weight of 6 kg while maintaining metabolic stability and successfully bridging to transplantation. Post-transplantation follow-up revealed stable growth, metabolic control, and no neurological complications. Conclusions The combined preclinical and clinical findings support HLC infusion as a viable bridge therapy for neonates with UCD, providing metabolic support to achieve safer weight thresholds for transplantation. While promising, careful monitoring remains essential, particularly for potential complications such as thrombus formation. Trial Registration jRCT, jRCT1090220412. Registered on 27 February 2019, https://jrct.niph.go.jp/en-latest-detail/jRCT1090220412 (originally registered in JMACCT (JMA-IIA00412)).

Keywords

• Hepatocyte
• Embryonic stem cells (ESCs)
• Urea cycle disorders (UCD)
• Liver transplantation
• Neonatal-onset
• Ammonia removal