Early Translational III
Although the liver can regenerate itself, chronic or overwhelming damage can cause life-threatening liver failure. Currently, the only therapy for liver failure is liver transplantation. Because the supply of cadaveric livers or liver tissue from living donors far exceeds the demand, physicians and researchers seek to develop new therapies to save the lives of patients with liver failure. One promising strategy is transplantation of hepatocytes, the cells of the liver that provide most of its functions and that are defective in liver failure. To make hepatocyte transplantation available to all patients who could benefit, a cell source other than scarce donor livers has to be established. In contrast to hepatocytes, skin cells can be readily obtained and expanded in culture. Therefore, the recent discovery that skin cells can be converted into hepatocytes by transfer of a few genes suggests a promising new source of hepatocytes. To develop transplantation of such cells as a therapy for liver failure, we aim to identify which readily available human cell type—skin, blood or fat cells—can be most efficiently converted into hepatocytes using methods of temporary gene transfer. Importantly, the therapeutic efficacy and safety of these induced hepatocytes will be rigorously tested in animal models of human liver failure. If successful, our project will establish the feasibility of therapy of liver failure with cells derived from a patient’s own readily available non-liver cells.
Statement of Benefit to California:
Like in most states in the US, the number of Californians in need of a liver transplant significantly exceeds the number of available donor organs. Most of these patients have liver cirrhosis due to hepatitis C infection, alcoholic liver disease or cholestatic diseases. Other indications for liver transplantation include acute liver failure, hepatitis B virus infection, metabolic liver diseases and cancer. While the incidence of these liver diseases has been relatively stable, non-alcoholic steatohepatitis (NASH), which was first described only 10 years ago, is rapidly emerging and predicted to become the leading indication for liver transplantation in the future. Because Hispanics have an increased risk of developing NASH, California, the state with the largest Hispanic population in the US, will be particularly impacted by this epidemic. Thus, developing an abundant source of cells for liver cell therapy, as proposed in this project, will not only benefit the Californians currently awaiting liver transplantation, but may also help the state’s medical system to respond to this future challenge.
The goal of this Development Candidate Feasibility project is to develop a source of autologous therapeutic cells for patients with liver disease who otherwise would require a liver transplant. The applicant will first determine which type of easily accessible cell (skin, blood, or fat cells) can be most efficiently converted into liver hepatocytes using transient gene transfer methods. Efforts will then focus on optimization of yield and quality for the production of induced hepatocyte-like cells (iHep). To demonstrate proof of concept, the efficacy and safety of the resulting iHep cells then will be tested in small and large animal models of liver failure. Objective and Milestones - The Target Product Profile was viewed as well defined. - The application lays out a scientifically ambitious but reasonable program. - Milestones are clear and logical. Rationale and Significance - The rationale for the approach is logical and compelling and is based on exciting new work by the applicant. - This work represents a potentially important means of generating therapeutic hepatocytes. - The choice of proposed disease indication is logical. Although the project does not yet address the most prevalent liver diseases, it would still have great potential impact on an unmet medical need. - The proposed studies may have application to other diseases; if successful, this proposal will move the field forward. Research Project Feasibility and Design - Reviewers agreed that significant preliminary data was a major strength of the proposal. It was also noted that the derivation of iHep cells from human embryonic fibroblasts was demonstrated convincingly, although generation from human adult cells has yet to be shown. - The research plan is focused, well designed, and, in conjunction with the preliminary results, addresses all activities necessary to lead towards a development candidate. - Reviewers felt that the timeline may be overly optimistic. - There was some concern about the clinical relevance of the proposed animal models of liver failure and about the feasibility of the immune suppression regimen for the large animal model. Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - The PI has an outstanding track record and is a leader in the field. - The quality of the research team and collaborators were viewed as a key strength of the application; team members have contributed significantly to the preliminary data presented. Collaborations, Assets, Resources and Environment No relevant concerns were highlighted by reviewers under this review criterion. Responsiveness to the RFA No relevant concerns were highlighted by reviewers under this review criterion.