Hyperammonemia is a metabolic disturbance characterized by anexcess of ammonia in the blood, and is a dangerous condition that leads tomental retardation. Primaryhyperammonemia is caused by inborn errors of metabolism such asornithine transcarbamylase (OTC) and carbamoyl phosphate synthetase I inthe urea cycle.OTC deficiency (OTCD) is an X-chromosome-linked disorder and is severe inhemizygous boys. Hemizygous boys often develop this disease during the neonatalperiod, and the patient often dies during this period. Living donor livertransplantation has been indicated for neonatal-onset type OTCD, and outcomesare favorable. However, neurological impairment associated with hyperammnonemicepisode of OTCD often occurs before liver transplantation that is usuallyperformed at an age of 5 months. For bridging to liver transplantation, we aimto perform embryonic stem cell-based therapy to a patient with OTCD to preventhyperammonemia. To this end, we prepared hepatocytes derived from humanembryonic stem cells as an investigational new drug. Sequencing analysis revealed that theembryonic stem cells as a raw material have intact the urea cycle-associated enzymes.The products expressed enzymes and exhibited metabolic activity of ammonia invitro. To perform proof of concept (POC) studies in a disease model, wegenerated immunodeficient mice with OTCD, which can receive human embryonicstem cell-derived products. In addition, we generated OTCD pig by the nucleartransfer technique to establish treatment protocol and surgical procedure. Drug(cell) disposition can be determined by using these animals. In this study, we introduceresults of our preclinical POC data and non-clinical pharmacology andtoxicology.
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