Jochen Meyburg1, Thomas Opladen2, Ute Spiekerkötter3,4, Andrea Schlune3, Jens-Peter Schenk5, Jan Schmidt6, Jürgen Weitz6, Jürgen Okun2, Friederike Bürger2, Tawfeg Ben Omran7, Ghassan Abdoh7, Hilal Al Rifai7, Ahmad Monavari8, Vassiliki Konstantopoulou9, Stefan Kölker2, Marc Yudkoff10, Georg F Hoffmann2. 1. Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany. jochen.meyburg@med.uni-heidelberg.de. 2. Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany. 3. Department of General Pediatrics, Neonatology and Paediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany. 4. Division of General Pediatrics, University Children's Hospital, Freiburg, Germany. 5. Division of Pediatric Radiology, Department of Diagnostic and Interventional Radiology, University Hospital, Heidelberg, Germany. 6. Department of Visceral and Transplant Surgery, University Hospital, Heidelberg, Germany. 7. Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar. 8. National Centre of Inherited Metabolic Disorders, Dublin, Ireland. 9. Division of Pulmonology, Allergology, Endocrinology, and Metabolic Medicine, University Children's Hospital, Vienna, Austria. 10. Division of Metabolic Diseases, Children's Hospital of Philadelphia, Philadelphia, USA.
Abstract
BACKGROUND: Urea cycle disorders (UCDs) still have a poor prognosis despite several therapeutic advancements. As liver transplantation can provide a cure, liver cell therapy (LCT) might be a new therapeutic option in these patients. METHODS: Twelve patients with severe UCDs were included in this prospective clinical trial. Patients received up to six infusions of cryopreserved human heterologous liver cells via a surgically placed catheter in the portal vein. Portal vein pressure, portal vein flow, and vital signs were monitored continuously. Calcineurin inhibitors and steroids were used for immunosuppression. In four patients, ureagenesis was determined with stable isotopes. Number and severity of hyperammonemic events and side effects of immunosuppression were analyzed during an observation period of up to 2 years. RESULTS: No study-related mortality was observed. The application catheter dislocated in two children. No significant side effects of catheter application or cell infusion were noted in the other ten patients. The overall incidence of infections did not differ significantly from a historical control group, and no specific side effects of immunosuppression were found. Seven patients were treated per protocol and could be analyzed for efficacy. Severe metabolic crises could be prevented in all of these patients, moderate crises in four of seven. Ureagenesis increased after cell infusion in all patients investigated. CONCLUSIONS: We found a favorable safety profile with respect to catheter placement, intraportal liver cell infusion, and immunosuppression. More than half of the children treated per protocol experienced metabolic stabilization and could be safely bridged to liver transplantation.
BACKGROUND:Urea cycle disorders (UCDs) still have a poor prognosis despite several therapeutic advancements. As liver transplantation can provide a cure, liver cell therapy (LCT) might be a new therapeutic option in these patients. METHODS: Twelve patients with severe UCDs were included in this prospective clinical trial. Patients received up to six infusions of cryopreserved human heterologous liver cells via a surgically placed catheter in the portal vein. Portal vein pressure, portal vein flow, and vital signs were monitored continuously. Calcineurin inhibitors and steroids were used for immunosuppression. In four patients, ureagenesis was determined with stable isotopes. Number and severity of hyperammonemic events and side effects of immunosuppression were analyzed during an observation period of up to 2 years. RESULTS: No study-related mortality was observed. The application catheter dislocated in two children. No significant side effects of catheter application or cell infusion were noted in the other ten patients. The overall incidence of infections did not differ significantly from a historical control group, and no specific side effects of immunosuppression were found. Seven patients were treated per protocol and could be analyzed for efficacy. Severe metabolic crises could be prevented in all of these patients, moderate crises in four of seven. Ureagenesis increased after cell infusion in all patients investigated. CONCLUSIONS: We found a favorable safety profile with respect to catheter placement, intraportal liver cell infusion, and immunosuppression. More than half of the children treated per protocol experienced metabolic stabilization and could be safely bridged to liver transplantation.
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