nach oben

Erschienen in:

12.10.2017 | Original Article

Human heterologous liver cells transiently improve hyperammonemia and ureagenesis in individuals with severe urea cycle disorders

verfasst von: Jochen Meyburg, Thomas Opladen, Ute Spiekerkötter, Andrea Schlune, Jens-Peter Schenk, Jan Schmidt, Jürgen Weitz, Jürgen Okun, Friederike Bürger, Tawfeg Ben Omran, Ghassan Abdoh, Hilal Al Rifai, Ahmad Monavari, Vassiliki Konstantopoulou, Stefan Kölker, Marc Yudkoff, Georg F. Hoffmann

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 1/2018

Einloggen, um Zugang zu erhalten

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.

Nur mit Berechtigung zugänglich

Alexandrova K, Griesel C, Barthold M et al (2005) Large-scale isolation of human hepatocytes for therapeutic application. Cell Transplant 14:845–853CrossRef

Allen KJ, Mifsud NA, Williamson R, Bertolino P, Hardikar W (2008) Cell-mediated rejection results in allograft loss after liver cell transplantation. Liver Transpl 14:688–694CrossRef

Ambrosino G, Varotto S, Strom SC et al (2005) Isolated hepatocyte transplantation for Crigler-Najjar syndrome type 1. Cell Transplant 14:151–157CrossRef

Dhawan A, Mitry RR, Hughes RD et al (2004) Hepatocyte transplantation for inherited factor VII deficiency. Transplantation 78:1812–1814CrossRef

Dhawan A, Puppi J, Hughes RD, Mitry RR (2010) Human hepatocyte transplantation: current experience and future challenges. Nat Rev Gastroenterol Hepatol 7:288–298CrossRef

Enns GM, Millan MT (2008) Cell-based therapies for metabolic liver disease. Mol Genet Metab 95:3–10CrossRef

Enosawa S, Horikawa R, Yamamoto A et al (2014) Hepatocyte transplantation using a living donor reduced graft in a baby with ornithine transcarbamylase deficiency: a novel source of hepatocytes. Liver Transpl 20:391–393CrossRef

European Medicines Agency (2014) Guideline on good pharmacovigilance practices (GVP). In: Guideline on good pharmacovigilance practices (GVP). European Medicines Agency, London

Fox IJ, Chowdhury JR, Kaufman SS et al (1998) Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 338:1422–1426CrossRef

Haberle J, Boddaert N, Burlina A et al (2012) Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 7:32CrossRef

Horslen SP, McCowan TC, Goertzen TC et al (2003) Isolated hepatocyte transplantation in an infant with a severe urea cycle disorder. Pediatrics 111:1262–1267CrossRef

Jorns C, Nowak G, Nemeth A et al (2016) De novo donor-specific HLA antibody formation in two patients with Crigler-Najjar syndrome type I following human hepatocyte transplantation with partial hepatectomy preconditioning. Am J Transplant 16:1021–1030CrossRef

Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003) Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med 349:1157–1167CrossRef

Kolker S, Valayannopoulos V, Burlina AB et al (2015) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis 38:1059–1074CrossRef

Leonard JV, McKiernan PJ (2004) The role of liver transplantation in urea cycle disorders. Mol Genet Metab 81(Suppl 1):S74–S78CrossRef

Meyburg J, Hoffmann GF (2010) Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects. Mol Genet Metab 100(Suppl 1):S77–S83CrossRef

Meyburg J, Hoerster F, Weitz J, Hoffmann GF, Schmidt J (2008) Use of the middle colic vein for liver cell transplantation in infants and small children. Transplant Proc 40:936–937CrossRef

Meyburg J, Alexandrova K, Barthold M et al (2009a) Liver cell transplantation: basic investigations for safe application in infants and small children. Cell Transplant 18:777–786CrossRef

Meyburg J, Das AM, Hoerster F et al (2009b) One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation 87:636–641CrossRef

Meyburg J, Hoerster F, Schmidt J, Poeschl J, Hoffmann GF, Schenk JP (2010) Monitoring of intraportal liver cell application in children. Cell Transplant 19:629–638CrossRef

Mitry RR, Dhawan A, Hughes RD et al (2004) One liver, three recipients: segment IV from split-liver procedures as a source of hepatocytes for cell transplantation. Transplantation 77:1614–1616CrossRef

Nettesheim S, Kolker S, Karall D et al (2017) Incidence, disease onset and short-term outcome in urea cycle disorders—cross-border surveillance in Germany, Austria and Switzerland. Orphanet J Rare Dis 12:111CrossRef

Ng VL, Alonso M, Bezerra JA (2000) Hepatocyte transplantation. Advancing biology and treating children. Clin Liver Dis 4:929–945 viiCrossRef

Opladen T, Lindner M, Das AM et al (2016) In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis. Mol Genet Metab 117:19–26CrossRef

Puppi J, Tan N, Mitry RR et al (2008) Hepatocyte transplantation followed by auxiliary liver transplantation—a novel treatment for ornithine transcarbamylase deficiency. Am J Transplant 8:452–457CrossRef

Quaglia A, Lehec SC, Hughes RD et al (2008) Liver after hepatocyte transplantation for liver-based metabolic disorders in children. Cell Transplant 17:1403–1414CrossRef

Ribes-Koninckx C, Ibars EP, Agrasot MA et al (2012) Clinical outcome of hepatocyte transplantation in four pediatric patients with inherited metabolic diseases. Cell Transplant 21:2267–2282CrossRef

Sokal EM, Smets F, Bourgois A et al (2003) Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-up. Transplantation 76:735–738CrossRef

Stephenne X, Najimi M, Smets F, Reding R, de Goyet JV, Sokal EM (2005) Cryopreserved liver cell transplantation controls ornithine transcarbamylase deficient patient while awaiting liver transplantation. Am J Transplant 5:2058–2061CrossRef

Stephenne X, Najimi M, Sibille C, Nassogne MC, Smets F, Sokal EM (2006) Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency. Gastroenterology 130:1317–1323CrossRef

Stephenne X, Debray FG, Smets F, et al (2012) Hepatocyte transplantation using the domino concept in a child with Tetrabiopterin non-responsive phenylketonuria. Cell Transplant 21:2765-2770CrossRef

Strom SC, Fisher RA, Rubinstein WS et al (1997) Transplantation of human hepatocytes. Transplant Proc 29:2103–2106CrossRef

Unsinn C, Das A, Valayannopoulos V et al (2016) Clinical course of 63 patients with neonatal onset urea cycle disorders in the years 2001-2013. Orphanet J Rare Dis 11:116CrossRef

Titel: Human heterologous liver cells transiently improve hyperammonemia and ureagenesis in individuals with severe urea cycle disorders
verfasst von: Jochen Meyburg
Thomas Opladen
Ute Spiekerkötter
Andrea Schlune
Jens-Peter Schenk
Jan Schmidt
Jürgen Weitz
Jürgen Okun
Friederike Bürger
Tawfeg Ben Omran
Ghassan Abdoh
Hilal Al Rifai
Ahmad Monavari
Vassiliki Konstantopoulou
Stefan Kölker
Marc Yudkoff
Georg F. Hoffmann
Publikationsdatum: 12.10.2017
Verlag: Springer Netherlands
Erschienen in: Journal of Inherited Metabolic Disease / Ausgabe 1/2018
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-017-0097-4

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

19.04.2024 | Vorhofflimmern | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Human heterologous liver cells transiently improve hyperammonemia and ureagenesis in individuals with severe urea cycle disorders

Abstract

Background

Methods

Results

Conclusions

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Update Innere Medizin

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Background

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2018

Phenotype, disease severity and pain are major determinants of quality of life in Fabry disease: results from a large multicenter cohort study

Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus

Lipoprotein-associated phospholipase A2 activity in obese adolescents with and without type 2 diabetes

Erratum to: Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project

Understanding childhood diabetes mellitus: new pathophysiological aspects

Erratum to: The presence of anaemia negatively influences survival in patients with POLG disease

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Update Innere Medizin