Maria Mercedes Binda, Elisa Corritore, Lisa Menchi, Tuba Baran, Yan Greiling, Sébastien Michel, John Tchelingerian, Giuseppe Mazza & Etienne Sokal
Clinical-grade human liver mesenchymal stem cells reduce NAS score and fibrosis progression in advanced stage NASH pre-clinical model through immunomodulation
Background and Aims: Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic liver diseases (NAFLD), is one of the prominent liver diseases worldwide. There is currently no approved drug for its treatment and liver transplantation is the only therapeutic approach for advanced NASH. Mesenchymal stem cells (MSCs) are promising candidates to modulate the pro-inflammatory and profibrogenic environment of chronic liver because of their immunomodulatory properties. HepaStem, adult human liver-derived MSCs isolated from organs unsuitable for transplantation can be GMPmanufactured, cryopreserved and reconstituted at the bedside as an off-the-shelf product. We previously showed that HepaStem can significantly reduce NAS score and collagen deposition in early stage NASH STAM™ model with necropsy at week 9 (Gellynck K et al 2016). Safety and tolerability have been shown in a phase I/II clinical trial in patients with metabolic disorders. The aim of this study is to evaluate the efficacy of HepaStem in an advanced stage NASH pre-clinical model.
Method: The preclinical NASH mouse model was induced by 2 hits such as streptozotocin at 2 days of age and high-fat diet from 4 weeks of age (first cell infusion at week 10 and necropsy at week 13 STAM™ model). The potency of HepaStem was compared to a vehicle co-administered with immunosuppression (cyclosporine) in order to reduce the potential xenogenic response of the recipient to human cells. As outcome, a NAFLD activity score system, which contains the steatosis, inflammation and ballooning scores, was evaluated.
Results: In an advanced stage NASH model, cell-based treatment (1 and 3 IV injections 12.5x106 cells/kg) significantly and dose-dependently decreased NAFLD activity score (22.4% vs 32.6% reduction, p<0.05 and p<0.001, respectively), which was mainly attributed to a significant reduction in inflammation and thus supporting the proposed mechanism of action (Inflammation score: vehicle vs 3 doses of HepaStem: p<0.01). In addition, HepaStem (1 and 3 IV injections 12.5x106 cells/kg) cellbased treatment tended to reduce the fibrotic area thus suggesting an inhibition of disease progression in a more advanced NASH model.
Conclusion: In line with our previous results (Gellynck K et al 2016), we confirm that clinical grade liver progenitor cells have anti-NASH and may have anti-fibrosis effects in an advanced pre-clinical NASH model. This observation provides significant evidences to open new phase I/II studies including also more severe NASH patients as well as to apply MSCs for the treatment of chronic liver disorders.
Reference: Gellynck K, Rommelaere G, Najimi M, Tchelingerian J, Lombard C, Thonnard J, Mazza G, Sokal, E. Clinical-grade human liver mesenchymal stem cells for the treatment of NASH-Fibrosis through immunomodulation. Presented at American Association for the Study of Liver Diseases, November 11-15, 2016, Boston, MA.