Preclinical research and clinical program in cell-based therapies for regenerative medicine application, primarily for acute and congenital liver diseases.
I have always been keenly investigating new, advanced treatments for liver disease. I started my post-graduate studies on cell-based treatments for liver disease in Italy, and later invited to join Dr Strom’s team (University of Pittsburgh Medical Center, PA-USA), the first to perform allogenic hepatocyte transplantation in patients with acute or chronic disorders. Working together, we promptly became the first facility to be approved by the US-FDA to isolate and transplant human hepatocytes. I have been playing prominent role in planning, developing and finalizing all the methodological and regulatory issues to translate cellular therapies into clinic, first in Italy, then in USA, and now at KI. During my PhD studies, I identified and proposed new solutions for several roadblocks preventing additional clinical results in hepatocyte transplants. Established that the main limiting factor in hepatocyte transplant is the availability of useful cells, I focused my energy to identify alternative sources for mature and functional hepatocytes, such as cells isolated from non-heart beating donors, or explanted liver tissues (‘domino liver cell strategy’), or fetal and neonatal human hepatocytes. All the validated cell sources were lately successfully translated in clinical programs (by our group and others’). So far, only one type of human stem cells has satisfied safety and efficacy requirements, rescuing life-threatening preclinical models of acute and congenital human liver diseases: epithelial cells isolated from amnion membrane in full-term placentae. Our group is active in translating such new stem cell therapy to the clinic, where for the first time we can inject primary allogenic stem cells without immunosuppression in support.
Our group has always been on the front line for the treatment of acute and congenital liver disorders by cell-based therapies. We dedicated our efforts in the advancement of cell-based therapies for liver diseases, with hepatocyte transplant as a bridge or an alternative to orthotopic liver transplantation. Since the main limiting factor in the use of human hepatocyte as a clinical therapy is the availability of useful cells from livers deemed unsuitable for transplantation, we focused our attention on alternative sources, with greatest results obtained by transplantation of amnion epithelial cells.
Our group was the first to report the stem cell nature and outstanding potential of placental amnion epithelial (AE) cells. We developed protocols for AE isolation and hepatic differentiation. Based on AE safety, technical feasibility, reduced economic cost, and the lack of ethical issues, we standardized protocols for AE isolation under GMP conditions, and efficient delivery route for clinical transplant. The use of relevant experimental models is of undeniable importance to examine the efficacy and safety of the product; thus, we validated the potential of AE therapy in different life-threatening models of liver disease. In collaboration with my Mentor (prof. Strom), we reported the most detailed study and correction of the amino acid and neurotransmitter abnormalities ever reported by a human stem cell. Preclinical data suggest that, although not the patient’s own cells, AE cells will likely not require immunosuppression. In support to allogenic use of AE cells without immunosuppression, during the past years we identified and described different molecular pathways constitutively expressed by these cells which may lead to a new, unlimited source of stem cells for regenerative medicine approaches, not only liver-specific. If forthcoming clinical trials bear this out, this is a paradigm shift for allogeneic cell transplantation, where the risk of side effects of immunosuppression is removed. This would allow AE therapy to be extended to tens of thousands of patients currently not considered for organ or cell transplant, as young/elder patients or congenital errors of metabolism.