Françoise Smets1, Dries Dobbelaere2, Patrick McKiernan3, Carlo Dionisi-Vici4, Pierre Broué5, Emmanuel Jacquemin6, Ana Isabel Lopes7, Isabel Gonçalves8, Hanna Mandel9, Joanna Pawlowska10, Diana Kamińska10, Eyal Shteyer11, Giuliano Torre4, Riki Shapiro12, François Eyskens13, Philippe Clapuyt14, Paul Gissen15, Danièle Pariente16, Stephanie Grunewald17, Marc Yudkoff18, Maria Mercedes Binda19, Mustapha Najimi20,19, Nathalie Belmonte19, Beatrice de Vos19, Joelle Thonnard19, Etienne Sokal1,19. 1. Department of Paediatrics, Paediatric Gastroenterology and Hepatology Unit, Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium. 2. Medical Reference Center for Inherited Metabolic Diseases, University Children's Hospital Jeanne de Flandre and RADEME Research Team for Rare Metabolic and Developmental Diseases, EA 7364, University Lille 2, CHRU Lille, Lille, France. 3. Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom. 4. Department of Hepatology, Gastroenterology and Nutrition, Ospedale Pediatrico Bambino Gesù di Roma, Roma, Italy. 5. Hépatologie pédiatrique et maladies héréditaires du métabolisme, Centre de compétences maladies héréditaires du métabolisme, Hôpital des enfants, CHU Toulouse, France. 6. Pediatric Hepatology and Liver Transplantation Unit, Reference Centre for Rare Liver Diseases, CHU Bicêtre, Assistance Publique, Hôpitaux de Paris, DHU Hepatinov, INSERM 1174, University Paris Sud, Paris, France. 7. Department of Pediatrics, Gastroenterology Unit, Medical Faculty of Lisbon, University Hospital Santa Maria, Lisbon, Portugal. 8. Hospital Pediátrico de Coimbra, Centro Hospitalar da Universidade de Coimbra, Coimbra, Portugal. 9. Department of Pediatrics, Metabolic Unit, Rambam Medical Center, Meyer Children's Hospital, Haifa, Israel. 10. Department of Gastroenterology, Hepatology and Nutritional Disorders, The Children's Memorial Health Institute, Warsaw, Poland. 11. Department of Pediatrics, Hadassah Ein-Kerem Medical Center, Jerusalem, Israel. 12. Liver Transplantation Unit, Institute of Gastroenterology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel. 13. Paediatric department, Universitair Ziekenhuis Antwerpen, Edegem, Belgium. 14. Department of Radiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. 15. GOSH UCL Biomedical Center, UCL Great Ormond Street Institute of Child Health, London, United Kingdom. 16. Department of Radiology, CHU Bicêtre, Le Kremlin Bicêtre, France. 17. Centre for Inborn Errors of Metabolism, Great Ormond Street Hospital and Institute of Child Health, UCL, London, United Kingdom. 18. Mass Spectroscopy Center, The Children's Hospital of Philadelphia, Philadelphia, USA. 19. Promethera Biosciences, Mont-Saint-Guibert, Belgium. 20. Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
Abstract
BACKGROUND: Regenerative medicine using stem cell technology is an emerging field that is currently tested for inborn and acquired liver diseases. OBJECTIVE: This phase I/II prospective, open label, multicenter, randomized trial aimed primarily at evaluating the safety of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem) in pediatric patients with urea cycle disorders (UCDs) or Crigler-Najjar (CN) syndrome 6 months posttransplantation. The secondary objective included the assessment of safety up to 12 months postinfusion and of preliminary efficacy. METHODS:Fourteen patients with UCDs and 6 with CN syndrome were divided into 3 cohorts by body weight and intraportally infused with 3 doses of HepaStem. Clinical status, portal vein hemodynamics, morphology of the liver, de novo detection of circulating anti-human leukocyte antigen antibodies, and clinically significant adverse events (AEs) and serious adverse events to infusion were evaluated by using an intent-to-treat analysis. RESULTS: The overall safety of HepaStem was confirmed. For the entire study period, patient-month incidence rate was 1.76 for the AEs and 0.21 for the serious adverse events, of which 38% occurred within 1 month postinfusion. There was a trend of higher events in UCD as compared with CN patients. Segmental left portal vein thrombosis occurred in 1 patient and intraluminal local transient thrombus in a second patient. The other AEs were in line with expectations for catheter placement, cell infusion, concomitant medications, age, and underlying diseases. CONCLUSIONS: This study led to European clinical trial authorization for a phase II study in a homogeneous patient cohort, with repeated infusions and intermediate doses.
RCT Entities:
BACKGROUND: Regenerative medicine using stem cell technology is an emerging field that is currently tested for inborn and acquired liver diseases. OBJECTIVE: This phase I/II prospective, open label, multicenter, randomized trial aimed primarily at evaluating the safety of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem) in pediatric patients with urea cycle disorders (UCDs) or Crigler-Najjar (CN) syndrome 6 months posttransplantation. The secondary objective included the assessment of safety up to 12 months postinfusion and of preliminary efficacy. METHODS: Fourteen patients with UCDs and 6 with CN syndrome were divided into 3 cohorts by body weight and intraportally infused with 3 doses of HepaStem. Clinical status, portal vein hemodynamics, morphology of the liver, de novo detection of circulating anti-human leukocyte antigen antibodies, and clinically significant adverse events (AEs) and serious adverse events to infusion were evaluated by using an intent-to-treat analysis. RESULTS: The overall safety of HepaStem was confirmed. For the entire study period, patient-month incidence rate was 1.76 for the AEs and 0.21 for the serious adverse events, of which 38% occurred within 1 month postinfusion. There was a trend of higher events in UCD as compared with CN patients. Segmental left portal vein thrombosis occurred in 1 patient and intraluminal local transient thrombus in a second patient. The other AEs were in line with expectations for catheter placement, cell infusion, concomitant medications, age, and underlying diseases. CONCLUSIONS: This study led to European clinical trial authorization for a phase II study in a homogeneous patient cohort, with repeated infusions and intermediate doses.
Authors: Yanina Bogliotti; Mark Vander Roest; Aras N Mattis; Robert G Gish; Gary Peltz; Robin Anwyl; Salah Kivlighn; Eric R Schuur Journal: Cells Date: 2022-06-22 Impact factor: 7.666
Authors: Louise Coppin; Mustapha Najimi; Julie Bodart; Marie-Sophie Rouchon; Patrick van der Smissen; Stéphane Eeckhoudt; Géraldine Dahlqvist; Diego Castanares-Zapatero; Mina Komuta; Sanne L Brouns; Constance C Baaten; Johan W M Heemskerk; Sandrine Horman; Nathalie Belmonte; Etienne Sokal; Xavier Stéphenne Journal: Cells Date: 2019-08-07 Impact factor: 6.600