Towards Clinically-Relevant Cell-Transplant-Based Therapies for the Treatment of Liver Diseases
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Between 30-40 million Americans are afflicted with liver disease, and the number of fatalities is climbing. Many patients with liver disease have benefited from orthotopic liver transplantation (OLT), but to a majority of these patients, OLT remains unavailable because of the shortage of donor organs and the cost of the procedure. To treat more patients and to lessen their burden, hepatocyte transplantation (HT) has been proposed as a substitute for OLT. Like OLT, HT could become a viable approach to regain hepatic function. However, three major hurdles have prevented large-scale clinical application of HT: (a) availability of transplantable hepatocytes; the supply of human hepatocytes is similar to OLT, (b) Lack of safe and efficient tools for ex vivo gene therapy, and (c) Engraftment and repopulation efficiency; simple HT via cell administration with no other treatments rarely results in substantial integration of the cells into the liver, so repopulation of the host liver with transplanted hepatocytes remains too low for therapeutic benefit. However, preparative treatments for HT have been designed that improve engraftment and repopulation by inducing hepatocytic proliferation and giving transplanted cells a proliferative advantage. Here I write about the history of preparative treatments, what is necessary to translate these to clinical application, and how close we are to doing this, and describe my work on the application of HT with preparative treatments based on hepatic irradiation (HIR) for the treatment of liver-centered metabolic disease. The use of HIR in the liver is associated with a high probability for radiation-induced-liver disease (RILD), which is potentially lethal - a toxicity which significantly limits the use of radiation for the treatment of liver tumors in patients with poor liver function and no other options. Therefore I include a substantial investigation of the literature on the topic of whole liver irradiation, partial liver irradiation, and the therapeutic options we have to treat RILD. I also describe our work on the use of a novel approach for RILD monitoring, protection, and treatment. In this work we have shown that a single course of treatment of HT following non-invasive, conformal HIR and administration of GC-1 (an FDA approved investigational drug) results in massive hepatic repopulation and provides a long term cure for monogeneic dyslipidemia by reducing serum cholesterol by ~80% (restoring it to normal levels) and preventing atherosclerotic changes in the aorta, the aortic valve, and coronary vessels. This work lays out the foundation for clinical investigations for HT for the treatment of metabolic liver diseases. To assess the main side effect of liver radiation, we have also developed a murine model for RILD following partial hepatic irradiation and used novel in-vivo biomarkers Hyaluronic Acid (measuring LSEC injury) and Technetium 99 SPELT-CT. To reliably quantitate RILD progression we created an algorithm that measures the residual size of the irradiated area that still demonstrates reduced perfusion. Using these endpoints we demonstrate that administration of a Thrombopoietin mimetic, in the context of transplantation of liver sinusoidal endothelial cells, results in sinusoidal repopulation in the irradiated liver and that this repopulation leads to approximately 82% reduction in the residual defect volume. This work has contributed tools for RILD monitoring, protection, and mitigation. I have also addressed the cell-supply shortage with an extensive review of the literature on potential cell sources including autologous hepatocytes, xenogeneic cells, allogeneic cells, and especially in-vitro generated human hepatocyte-like-cells. I also discuss my work on the design and generation of a clinically-applicable hepatocyte transdifferentiation vector consisting of 6 lineage-determining transcription factors in a single polycistronic 23kb non-integrating vector based on the Venezuelan Equine Encephalitis virus RNA replicon.
Source: Dissertations Abstracts International, Volume: 80-03, Section: B.;Publisher info.: Dissertation/Thesis.;Advisors: Guha, Chandan.