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

Abstract

BACKGROUND: Regenerative medicine using stem cell technology is an emerging therapy, addressing congenital and acquired diseases. Heterologous Human Adult Liver-derived Progenitor Cells (HHALPCs) have the potency to metabolise ammonium and conjugate bilirubin. Preclinical studies have shown the safety in vitro and in animal models. AIM: We report the safety and preliminary efficacy results of a multicenter phase I/II trial using HHALPCs in pediatric patients with urea cycles disorders (UCD's) or Crigler-Najjar (CN) syndrome METHODS: 14 urea cycle disorder patients and 6 Crigler-Najjar patients were included. Patients were divided in three weight cohort, and three dose levels. A dose escalation from the lowest to the highest dose was applied for the first three patients enrolled in each weight cohort.RESULTS: The safety profile observed was in line with the profile expected for this new cell therapy, the infusion procedure, the concomitant medications, the age group and the underlying disease. Partial left portal vein permanent thrombosis occurred in one patient. Preliminary efficacy data included de novo urea synthesis as demonstrated by the [ 13 C] ureagenesis test at 6 months follow-up versus baseline, engraftment of cells in 3 evaluable patients, and a decrease of bilirubin under similar phototherapy condition in 2 Crigler-Najjar patients.CONCLUSION: This study opens the way for a confirmatory study in a homogeneous cohort of patients with a defined treatment dose.Take-home message: This study reports general safety of Human Adult Liver-derived Progenitor Cells infusion in patients with severe metabolic diseases. Confirmation of efficacy will be addressed in a homogenous cohort of patients with a defined treatment dosis.

Clinical Protocol to Prevent Thrombogenic Effect of Liver-Derived Mesenchymal Cells for Cell-Based Therapies

“…To assess the effect of high dose infusion of HHALPCs, Wistar rats (n = 6/group) were infused with 5 × 10 7 cells/kg, a dose previously used in clinical trials for patients suffering from liver-based metabolic diseases [3,21]. The high dose infusion was compared to intermediate (1.25 × 10 7 cells/kg), and low (5 × 10 6 cells/kg) cell doses.…”

“…Anesthetized male Wistar Han rats (150–200 g) (n = 6/group) were transplanted in sterile conditions with one of three different cell dosages, 5 × 10 6 cells/kg, 1.25 × 10 7 cells/kg or 5 × 10 7 cells/kg, by intraportal injection, with or without intravenous administration of bivalirudin (0.75 mg/kg Angiox, Medicines Company, NJ, USA). The cell dose range originated from clinical cases of patients transplanted with HHALPCs [21,33] or hepatocytes [34,35]. For safety studies, the lowest cell dose, 5 × 10 6 cells/kg, was infused by intraportal and peripheral infusion.…”

“…In particular, HHALPCs are considered for unstable patients with liver-based inherited metabolic diseases, needing orthotopic liver transplantation; as due to the shortage of donors, the risks of surgery, and the need for lifelong immunosuppression the utility of transplantation is limited. The therapeutic goal of repeated HHALPCs infusions is to engraft and mature into hepatocyte-like cells, to provide the missing enzyme(s) for long-term correction of the metabolic defect, which so far have been achieved only by transplantation of large cell masses of allogenic hepatocyte (5 × 10 7 cells/kg or above) [3,21,22]. Additionally, due to their immunomodulatory [23] and anti-fibrotic effects [24], HHALPCs may also be used to treat acute decompensated cirrhotic (ADC) patients, in which transplantation of lower cell doses may be sufficient [25].…”

Human liver stem cells express UGT1A1 and improve phenotype of immunocompromised Crigler Najjar syndrome type I mice

“…HHALPCs delivery induced a ~ 20% decrease in bilirubin levels in 2 patients, one of whom (a female) showed successful liver engraftment of male stem cells. A transient effect was observed in another CNSI patient 34 . This study demonstrates the overall safety of liver-derived adult stem cells injection in CNSI patients, as well as in other severe metabolic liver diseases such as urea cycle disorder.…”

“…Importantly, a very recent study evaluated the safety of using human liver-derived stem cells, termed Heterologous Human Adult Liver-derived Progenitor Cells (HHALPCs), in CNSI patients in a phase I/II prospective trial 34 . During the treatment period, patients were subjected to phototherapy daily.…”