Adult liver progenitor cells for treating acute-onchronic liver failure

The invention relates to the use of a composition comprising human adult liver-derived progenitor cells, such as heterologous human adult liver-derived progenitor cells (HHALPC), for the treatment of a patient who has developed acute-on-chronic liver failure (ACLF) or is at risk of developing ACLF, wherein the treatment comprises a step of administering to said patient an amount of said composition which comprises a dose of 0.25 to 2.5 million said progenitor cells per kg body weight; wherein the composition is substantially free of an effective amount of an anticoagulant, and wherein the patient does not receive any co-treatment with an anticoagulant

Human Allogeneic Liver-Derived Progenitor Cells Significantly Improve NAFLD Activity Score and Fibrosis in Late-Stage NASH Animal Model

Accumulated experimental and clinical evidence supports the development of human allogeneic liver-derived progenitor cells (HALPCs) to treat fibro-inflammatory liver diseases. The aim of the present study was to evaluate their therapeutic effect in a non-alcoholic steatohepatitis (NASH)-STAM mouse model. The immune signaling characteristics of HALPCs were first assessed in vitro. Upon inflammation treatment, HALPCs secreted large amounts of potent bioactive prostaglandin E2 and indoleamine 2,3-dioxygenase, which significantly reduced CD4+ T-lymphocyte proliferation and secretion of proinflammatory cytokines. In vivo, HALPCs were intravenously administered as single or triple shots (of a dose of 12.5 × 106 cells/kg BW) in STAM mice. Transplantation of HALPCs was associated with a significant decrease in the NAFLD activity score at an early stage and in both inflammation and hepatocyte ballooning scores in late-stage NASH. Sirius red staining analyses revealed decreased collagen deposition in the pericentral region at both stages of NASH. Altogether, these findings showed the anti-inflammatory and anti-fibrotic features of HALPCs in an in vivo NASH model, which suggests their potential to reverse the progression of this chronic fibro-inflammatory disease

Liver transplantation does not impact the renal function outcome in Alagille syndrome

Background and Aims: Alagille syndrome (AS) is an autosomal dominant multi-systemic disorder caused by pathogenic variants in JAG1 and NOTCH2. Characteristic findings include hepatic involvement with bile duct paucity and 20-50% eventually need a liver transplantation. Post-LT Tacrolimus induced nephropathy is well recognised and 40% of AS patients have an underlying renal anomaly. In the current study we analysed the impact of LT and Tacrolimus on the evolution of renal function (RF) in children with AS. Methods: Retrospective study including 50 children that satisfied 3 of 5 major Alagille syndrome criteria and under regular follow-up at our centre between 1984 and 2016. Clinical, biochemical and radiological data were collected at similar time points of follow-up among the transplanted and non-transplanted children. The time points were at diagnosis or at LT and after 1-2 years, 2-3 years, 3-5 years, 5-7 years and 7-10 years of follow-up. The RF was estimated by glomerular filtration rate (eGFR) using the updated Schwartz formula. The RF outcomes of children with AS having undergone LT were compared with those without LT and also with children having undergone LT for non-AS related indication but without associated nephropathy. Results: 28 of 50 (56%) included AS children underwent LT and were compared with 77 children transplanted for non-AS indications. Mean eGFR post-LT in AS patients and non-AS patients were 93.8 mL/min and 143.2 mL/min, respectively (difference: 49.4 mL/min, p<0.0001). Among children with AS mean eGFR observed in those who did not receive LT was 87.9 mL/min, -5.9 mL/min compared to those who received LT though this was statistically insignificant (p=0.32). Presence of renal ultrasound abnormalities was correlated to RF impairment in AS patients, with or without LT: -14.6 mL/min (98.5 mL/min vs 83.9 mL/min, p=0.03) and -40.9 mL/min (97.8 mL/min vs 56.9 mL/min, p<0.0001), respectively. Conclusions: Post-LT renal function outcomes are significantly worse in children with AS being the primary disease. Among the children with AS, the RF outcome is not worse after LT

Liver transplantation does not impact the renal function outcome in Alagille syndrome

Objectives and study: Alagille syndrome (AS) is an autosomal dominant multi-systemic disorder caused by pathogenic variants in JAG1 and NOTCH2. Characteristic findings include hepatic involvement with bile duct paucity and 20-50% eventually need a liver transplantation. Post-LT Tacrolimus induced nephropathy is well recognised and 40% of AS patients have an underlying renal anomaly. In the current study we analysed the impact of LT and Tacrolimus on the evolution of renal function (RF) in children with AS. Methods: Retrospective study including 50 children that satisfied 3 of 5 major Alagille syndrome criteria and under regular follow-up at our centre between 1984 and 2016. Clinical, biochemical and radiological data were collected at similar time points of follow-up among the transplanted and non-transplanted children. The time points were at diagnosis or at LT and after 1-2 years, 2-3 years, 3-5 years, 5-7 years and 7-10 years of follow-up. The RF was estimated by glomerular filtration rate (eGFR) using the updated Schwartz formula. The RF outcomes of children with AS having undergone LT were compared with those without LT and also with children having undergone LT for non-AS related indication but without associated nephropathy. Results: 28 of 50 (56%) included AS children underwent LT and were compared with 77 children transplanted for non-AS indications. Mean eGFR post-LT in AS patients and non-AS patients were 93.8 mL/min and 143.2 mL/min, respectively (difference: 49.4 mL/min, p<0.0001). Among children with AS mean eGFR observed in those who did not receive LT was 87.9 mL/min, -5.9 mL/min compared to those who received LT though this was statistically insignificant (p=0.32). Presence of renal ultrasound abnormalities was correlated to RF impairment in AS patients, with or without LT: -14.6 mL/min (98.5 mL/min vs 83.9 mL/min, p=0.03) and -40.9 mL/min (97.8 mL/min vs 56.9 mL/min, p<0.0001), respectively. Conclusion: Post-LT renal function outcomes are significantly worse in children with AS being the primary disease. Among the children with AS, the RF outcome is not worse after LT

Liver transplantation does not impact the renal function outcome in Alagille syndrome

Background and Aims: Alagille syndrome (AS) is an autosomal dominant multi-systemic disorder caused by pathogenic variants in JAG1 and NOTCH2. Characteristic findings include hepatic involvement with bile duct paucity and 20-50% eventually need a liver transplantation. Post-LT Tacrolimus induced nephropathy is well recognised and 40% of AS patients have an underlying renal anomaly. In the current study we analysed the impact of LT and Tacrolimus on the evolution of renal function (RF) in children with AS. Methods: Retrospective study including 50 children that satisfied 3 of 5 major Alagille syndrome criteria and under regular follow-up at our centre between 1984 and 2016. Clinical, biochemical and radiological data were collected at similar time points of follow-up among the transplanted and non-transplanted children. The time points were at diagnosis or at LT and after 1-2 years, 2-3 years, 3-5 years, 5-7 years and 7-10 years of follow-up. The RF was estimated by glomerular filtration rate (eGFR) using the updated Schwartz formula. The RF outcomes of children with AS having undergone LT were compared with those without LT and also with children having undergone LT for non-AS related indication but without associated nephropathy. Results: 28 of 50 (56%) included AS children underwent LT and were compared with 77 children transplanted for non-AS indications. Mean eGFR post-LT in AS patients and non-AS patients were 93.8 mL/min and 143.2 mL/min, respectively (difference: 49.4 mL/min, p<0.0001). Among children with AS mean eGFR observed in those who did not receive LT was 87.9 mL/min, -5.9 mL/min compared to those who received LT though this was statistically insignificant (p=0.32). Presence of renal ultrasound abnormalities was correlated to RF impairment in AS patients, with or without LT: -14.6 mL/min (98.5 mL/min vs 83.9 mL/min, p=0.03) and -40.9 mL/min (97.8 mL/min vs 56.9 mL/min, p<0.0001), respectively. Conclusions: Post-LT renal function outcomes are significantly worse in children with AS being the primary disease. Among the children with AS, the RF outcome is not worse after LT

A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation

Background &amp; Aims: Human allogeneic liver-derived progenitor cells (HALPC, HepaStem®; Promethera Biosciences, Mont-Saint-Guibert, Belgium) are an advanced therapy medicinal product that could potentially alleviate systemic inflammation and ameliorate liver function in patients with acute-on-chronic liver failure (ACLF) or acute decompensation of cirrhosis (AD). Methods: This open-label phase II study was conducted in 9 centres in Belgium, Spain, and Bulgaria between 2016 and 2019. The primary objective was to assess the safety of HALPC therapy up to Day 28 and the secondary objectives were to assess its safety and preliminary efficacy up to Month 3. Results: The 24 treated patients (mean age: 51 years) were mostly male with an alcoholic cirrhosis. On pre-infusion Day 1, 15 patients had ACLF and 9 patients had AD. Two of the 3 initial patients treated with high HALPC doses (∼5×106 cells/kg body weight [BW]) had severe adverse bleeding events attributed to treatment. In 21 patients subsequently treated with lower HALPC doses (0.6 or 1.2×106 cells/kg BW, 1 or 2 times 7 days apart), no serious adverse events were related to treatment, and the other adverse events were in line with those expected in patients with ACLF and AD. Overall, markers of systemic inflammation and altered liver function decreased gradually for the surviving patients. The Day-28 and Month-3 survival rates were 83% (20/24) and 71% (17/24), and at Month 3, no patient had ACLF. Conclusions: The treatment of patients with ACLF or AD with up to 2 doses of 1.2×106 HALPC/kg BW appeared safe. The results of this study support the initiation of a proof-of-concept study in a larger cohort of patients with ACLF to further confirm the safety and evaluate the efficacy of HALPC therapy. Clinical Trials Registration: EudraCT 2016-001177-32. Lay summary: Patients with liver cirrhosis may suffer from the rapid onset of organ failure or multiple organ failure associated with a high risk of death in the short term. This clinical study of 24 patients suggests that an advanced therapy based on the intravenous infusion of low doses of human allogeneic liver-derived progenitor cells is safe and supports the next phase of clinical development of this type of therapy