Abstract
Liver cirrhosis is the 6th leading cause of death in adults aged 15–59 years in high-income countries. For many who progress to cirrhosis, the only prospect for survival is liver transplantation. While there is some indication that mesenchymal stem cells may be useful in reversing established liver fibrosis, there are limitations to their widespread use – namely their rarity, the need for extensive serial passaging and the associated potential for genomic instability and cellular senescence. To this end, we propose the use of allogeneic amnion epithelial cells. This clinical trial will assess the safety of intravenously delivered allogeneic human amnion epithelial cells (hAECs) in patients with compensated liver cirrhosis. This will also provide clinical data that will inform phases 2 and 3 clinical trials with the ultimate goal of developing hAECs as a therapeutic option for patients with cirrhosis who are at significant risk of disease progression. We will recruit 12 patients with compensated cirrhosis, based on their hepatic venous pressure gradient, for a dose escalation study. Patients will be closely monitored in the first 24 h post-infusion, then via daily telephone interviews until clinical assessment on day 5. Long term follow up will include standard liver tests, transient elastography and hepatic ultrasound. Ethics approval was obtained from Monash Health for this trial 16052A, “A Pilot Study Evaluating the Safety of Intravenously Administered Human Amnion Epithelial Cells for the Treatment of Liver Fibrosis, A First in Adult Human Study.” The trial will be conducted in accordance to Monash Health Human Ethics guidelines. Outcomes from this study will be disseminated in the form of conference presentations and submission to a peer reviewed journal. This trial has been registered on the Australian and New Zealand Clinical Trials Registry ACTRN12616000437460.
Highlights
The World Health Organization has identified cirrhosis as the 6th leading cause of death in adults aged 15–59 years in high-income countries and the 9th most common cause of death in that age group in low-income countries (Lopez et al, 2006)
The purpose of this phase 1 trial is to investigate the safety of human amnion epithelial cells (hAECs) in patients with compensated cirrhosis
Liver transplantation is an established life-saving treatment for patients with end-stage liver disease; success depends on donor graft availability and recipients require life-long immunosuppression. hAEC based therapy overcomes both of these limitations due to widespread availability of the cells and the absence of a host immune response to the transplanted cells
Summary
The World Health Organization has identified cirrhosis as the 6th leading cause of death in adults aged 15–59 years in high-income countries and the 9th most common cause of death in that age group in low-income countries (Lopez et al, 2006). HAECs appear to influence inflammation and fibrosis by interacting with a multitude of cell types including fibroblasts (Vosdoganes et al, 2012), neutrophils (Tan et al, 2016), and macrophages (Manuelpillai et al, 2012; Tan et al, 2014) These outcomes appear to be independent of significant cell engraftment, but are instead indicative of a paracrine effect, similar to what has been previously reported in MSCs. Considering the complex cellular interactions involved in hepatic wound healing, hAECs may provide a multi-targeted approach needed for effective collagen degradation and hepatocyte regeneration. As of the preparation of this manuscript, five babies have received allogeneic hAECs with no safety concerns (ACTRN12614000174684) The objective of this phase 1 trial is to primarily assess the safety of intravenously delivered allogeneic hAECs in patients with compensated liver cirrhosis. HAEC based therapy has the potential to prevent progression of cirrhosis and the need for transplantation
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