Phase I/II Trial of Liver Derived Mesenchymal Stem Cells in Pediatric Liver Based Metabolic Disorders: A Prospective, Open Label, Multicenter, Partially Randomized, Safety Study of One Cycle of Heterologous Human Adult Liver-Derived Progenitor Cells (HepaStem®) in Urea Cycle Disorders and Crigler-Najjar Syndrome patients.

Smets, Françoise;Dobbelaere, Dries;McKiernan, Patrick;Dionisi-Vici, Carlo;Sokal, Etienne;et.al.
(2019) Progress in Transplantation — Vol. 103, n° 9, p. 1903-1915 (2019)

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Authors
  • Smets, FrançoiseUCLouvain
    Author
  • Dobbelaere, Dries
    Author
  • McKiernan, Patrick
    Author
  • Dionisi-Vici, Carlo
    Author
  • Clapuyt, PhilippeUCLouvain
    Author
  • Najimi, MustaphaUCLouvain
    Author
  • Sokal, EtienneUCLouvain
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Abstract
Background: Regenerative medicine using stem cell technology is an emerging field that is currently tested for inborn and acquired liver diseases. Aim: 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 post-transplantation. The secondary objective included the assessment of safety up to 12 months post-infusion, 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 three 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 (SAEs) 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 SAEs, of which 38% occurred within one month post-infusion. There was a trend of higher events in UCD as compared to CN patients. Segmental left portal vein thrombosis occurred in one 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. Conclusion: This study led to European clinical trial authorization for a phase II study in a homogeneous patient cohort, with repeated infusions and intermediate doses.
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Smets, F., Dobbelaere, D., McKiernan, P., Dionisi-Vici, C., Broué, P., Jacquemin, E., Lopes, A. I., Gonçalves, I., Mandel, H., Pawlowska, J., Kamińska, D., Shteyer, E., Torre, G., Shapiro, R., Eyskens, F., Clapuyt, P., Gissen, P., Pariente, D., Grunewald, S., et al. (2019). Phase I/II Trial of Liver Derived Mesenchymal Stem Cells in Pediatric Liver Based Metabolic Disorders: A Prospective, Open Label, Multicenter, Partially Randomized, Safety Study of One Cycle of Heterologous Human Adult Liver-Derived Progenitor Cells (HepaStem®) in Urea Cycle Disorders and Crigler-Najjar Syndrome patients. Progress in Transplantation, 103(9), 1903-1915. https://doi.org/10.1097/TP.0000000000002605 (Original work published 2019)