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

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

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.

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Abbreviations

ALSD:

Argininosuccinate lyase deficiency

ASSD:

Argininosuccinate synthetase deficiency

CPS1D:

Carbamoyl phosphate synthetase I deficiency

FV:

Final visit

LCT:

Liver cell therapy

OLT:

Orthotopic liver transplantation

OTCD:

Ornithine carbamoyltransferase deficiency

PVP:

Portal vein pressure

UCD:

Urea cycle disorder

Vmax :

Maximum flow velocity in the portal vein stem

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Funding

The clinical study was sponsored by Cytonet GmbH & Co. KG, Weinheim, Germany. The intellectual property rights to the clinical results were acquired by Promethera Biosciences S.A./N.V. in April 2016.

Author information

Author notes

  1. Jochen Meyburg and Thomas Opladen contributed equally to this work.

Authors and Affiliations

  1. Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany

    Jochen Meyburg, Thomas Opladen, Jürgen Okun, Friederike Bürger, Stefan Kölker & Georg F. Hoffmann

  2. Department of General Pediatrics, Neonatology and Paediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany

    Ute Spiekerkötter & Andrea Schlune

  3. Division of General Pediatrics, University Children’s Hospital, Freiburg, Germany

    Ute Spiekerkötter

  4. Division of Pediatric Radiology, Department of Diagnostic and Interventional Radiology, University Hospital, Heidelberg, Germany

    Jens-Peter Schenk

  5. Department of Visceral and Transplant Surgery, University Hospital, Heidelberg, Germany

    Jan Schmidt & Jürgen Weitz

  6. Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar

    Tawfeg Ben Omran, Ghassan Abdoh & Hilal Al Rifai

  7. National Centre of Inherited Metabolic Disorders, Dublin, Ireland

    Ahmad Monavari

  8. Division of Pulmonology, Allergology, Endocrinology, and Metabolic Medicine, University Children’s Hospital, Vienna, Austria

    Vassiliki Konstantopoulou

  9. Division of Metabolic Diseases, Children’s Hospital of Philadelphia, Philadelphia, USA

    Marc Yudkoff

Authors
  1. Jochen Meyburg
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  2. Thomas Opladen
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  3. Ute Spiekerkötter
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  4. Andrea Schlune
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  5. Jens-Peter Schenk
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  6. Jan Schmidt
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  8. Jürgen Okun
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  13. Ahmad Monavari
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  14. Vassiliki Konstantopoulou
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  15. Stefan Kölker
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  16. Marc Yudkoff
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  17. Georg F. Hoffmann
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Corresponding author

Correspondence to Jochen Meyburg.

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Conflict of interest

J. Meyburg, T. Opladen, and G. F. Hoffmann received travel grants from Cytonet GmbH, Weinheim, Germany.

Additional information

Communicated by: Bridget Wilcken

Electronic supplementary material

ESM 1

Primary and secondary endpoints of the study (DOCX 76.1 kb)

ESM 2

Inclusion and exclusion criteria (DOCX 92.0 kb)

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Meyburg, J., Opladen, T., Spiekerkötter, U. et al. Human heterologous liver cells transiently improve hyperammonemia and ureagenesis in individuals with severe urea cycle disorders. J Inherit Metab Dis 41, 81–90 (2018). https://doi.org/10.1007/s10545-017-0097-4

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  • DOI: https://doi.org/10.1007/s10545-017-0097-4

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