New Faculty Physician Scientist
The goal of this proposal is to develop stem cell based therapies for treatment of blindness due to corneal endothelial dysfunction. Cornea is the anterior-most, transparent structure of the eye, and the corneal endothelium, the inner layer of the cornea, functions as a pump that is necessary for maintaining corneal transparency and clear vision. Corneal endothelial dysfunction, a frequent cause of corneal blindness, is a common indication for corneal transplantation in developed nations. The latest eye bank statistics show that over 60,000 donor corneas were made available for transplantation in 2010 in the US, and the demand is expected to rise due to increasing age of the baby boomers. Stem cell based therapies offers a means of addressing the impending rise in demand fro donor corneas, but it is hindered by poorly understood corneal endothelial cell (CEC) development. This proposal will investigate the feasibility of using CEC precursors derived from human embryonic stem cells for transplantation. The CEC precursors will be identified from spontaneously differentiated hESC, grown in the laboratory, and tested to determine their utility for transplantation. The results of this proposal can potentially provide an unlimited supply of CEC for treatment of blindness secondary to corneal endothelial dysfunction.
Statement of Benefit to California:
California, in addition to being the most populous state, is also the state with the highest number of Cornea & External Disease subspecialists in the union. This indicates that there is a substantial population of patients with cornea problems in California, many of whom need cornea transplants. Successful translation of the results of this proposal will result in increased availability of corneas for transplantation, directly benefiting the people of California needing cornea transplants. This proposal will also help the state economy by relying on California suppliers whenever possible.
Executive Summary The research proposed by this application tests the premise that human embryonic stem cells (hESCs) can spontaneously differentiate in vitro to corneal endothelial cells (CECs), a cell population with therapeutic potential for treating blindness resulting from corneal endothelial dysfunction. The cornea is the transparent tissue located in the front of the eye, and corneal endothelial dysfunction is a common indication requiring a corneal transplant. To achieve the goals of this project, the Principal Investigator (PI) will first attempt to identify gene regulatory elements that are active during specification of CECs from a developmental progenitor population (Aim 1). Second, the PI will employ molecular and quantitative biological methods to test whether these elements can be exploited to identify CEC precursors derived from the spontaneous differentiation of hESCs in vitro (Aim 2). Finally, the PI will use a preclinical model of corneal dysfunction to evaluate the therapeutic potential of the derived CEC precursors (Aim 3). Research Plan - This proposal rests on the premise that appropriate gene regulatory elements would be identified from an early developmental lineage and would respond similarly in a differentiating hESC population. Reviewers considered the lack of preliminary data supporting this rationale to be a significant weakness. - The use of different model systems adds an unnecessary layer of complexity to the proposed experiments and introduces a potentially flawed assumption that each system would respond similarly or provide information that can be extrapolated across models. - Feasibility is substantially jeopardized by the dependency of each aim on the preceding one. - The applicant did not adequately justify the rationale for choosing hESC as a source of CECs over other human endothelial precursors that have been identified. - Reviewers questioned why only three markers were proposed for identifying CECs when many others have been used for this purpose. Moreover, the rationale for the choice of markers was not convincingly articulated. - If the proposed research were successful, creating a new cell source for CECs would represent a significant clinical advance for corneal regeneration. Principal Investigator - The PI has previously obtained research funding and has a track record of publications in human corneal disease, although many of the publications are case reports or clinical methodology rather than research papers. - The PI acknowledges his/her lack of stem cell biology expertise and proposes to address this issue with excellent collaborators, an outstanding mentor, and various courses. However, reviewers were concerned that the PI still lacked expertise with corneal stem cell biology and suggested that the applicant seek an additional mentor who is an expert in this area. - Reviewers criticized the ill-defined milestones in the career development plan but acknowledged the PI’s intent to establish him/herself as a translational physician scientist. Institutional Commitment - The institution has committed to protecting 90% of the PI’s time for research and provided laboratory space with administrative infrastructure. - The institution itself has made an extensive commitment to regenerative medicine and has a reputation in translational research. Also, the PI’s home department is one of the leading departments in its respective field in the country. Thus, the environment is excellent for the PI. - The letters of support are strong and reflect the institution’s commitment to the PI. Responsiveness - The application is responsive to the RFA, as it will generate CECs from hESCs by enhancing gene expression for CEC differentiation and subsequently, test the therapeutic potential of these cells.