Human Heterologous Liver Cells for Infusion in Children With Urea Cycle Disorders

Urea cycle disorders are rare inherited diseases that generally have a poor outcome, especially with onset of the disease in the neonatal period. UCDs are caused by a deficiency of one of six enzymes responsible for removing ammonia from the bloodstream. Instead of being converted into urea which is removed from the body with the urine, ammonia accumulates in UCD patients leading to brain damage or death. In the light of a mortality rate of > 50% at the age of 10 years the current pharmacological and dietary therapy is of modest success. Furthermore, mental retardation, cerebral palsy and other neurological sequelae are common among surviving patients.

In the last years, orthotopic liver transplantation (OLT) has become the best therapeutic option for UCD with long-term survival rates of about 90%. However, in the first weeks of life OLT still is technically demanding and prone to complications. With larger size of the recipient, the technical problems with OLT decrease considerably. The increased body weight usually achieved at the age of more than 8 weeks is related to a major reduction in transplantation related morbidity. Stabilization of metabolism until the patient can undergo OLT is essential.

In this study, neonates and infants with UCD will be included within the first 3 months of life and will be treated by repetitive application of human liver cells. In the last consequence, the aim of this new therapy option is to supply a sufficient amount of healthy liver cells to compensate for the metabolic defect and to reduce the risk of neurological deterioration while awaiting OLT.

Inclusion criteria

• Neonates and infants up to the age of ≤ 3 months with prenatally or postnatally confirmed urea cycle disorder and
• Children aged > 3 months up to ≤ 5 years of age with unstable metabolism and confirmed urea cycle disorder of either:

• Carbamylphosphate synthetase I [CPSD] or
• Ornithine transcarbamylase [OTCD] or
• Argininosuccinate synthetase [Citrullinaemia]
• A DNA analysis will further confirm diagnosis prior to or after inclusion according to the protocol.

• Accessibility of the portal vein
• Plasma ammonia level ≤ 250 μmol/l
• Written informed consent

Exclusion criteria

• Structural liver disease (cirrhosis, portal hypertension), or venoocclusive diseases
• Portal vein thrombosis
• Body Weight ≤3.5 kg
• Carrier of the human immuno-deficiency virus (HIV)
• Any other contraindication for immunosuppression
• Presence of acute infection at the time of inclusion
• Participation in other clinical trials or received experimental medication within the last 30 days
• Live vaccination planned during the course of the study
• Live vaccination within 4 weeks prior to beginning of study
• Allergic disposition against contrast medium used in study and/or antibiotics used in the manufacturing process
• Required valproate therapy
• Severe coagulopathy or thrombocytopenia
• Known diagnosis of hereditary thrombophilia (e.g. Factor V Leiden, Prothrombin 20210A variant) or parental history of hereditary thrombophilia and absense of thrombophilia testing in subject
• Cancer, severe systemic or chronic disease other than study indication (urea cycle deficiency)