New Faculty Physician Scientist
More than 3.2 million people worldwide are blind in both eyes due to corneal diseases. Limbal stem cell deficiency (LSCD) has been recognized as a major cause, either primary or secondary, of significant visual loss and blindness in many common corneal disorders. The corneal epithelium is constantly renewed and maintained by the limbal stem cells (LSCs) that are presumed to reside at the limbus, the junction between the cornea and conjunctiva. When LSCs are deficient and unable to repopulate the corneal surface, the cornea will become opaque. A corneal transplant is unable to survive and is contraindicated in LSCD. In patients who have LSCD in only one eye, LSCs can be obtained by a small biopsy from the healthy eye and expanded in culture. Transplantation of these expanded LSCs can restore sight in the affected eye. In patients who have LSCD in both eyes, LSCs will need to be regenerated from another cell source. The goal of the proposed research is to regenerate autologous LSCs from skin epithelial stem cells for transplantation. We plan to use a new method that provides the LSC niche factors necessary to maintain the corneal epithelial fate to facilitate the transdifferentiation of SESCs into LSCs. The efficiency of the transdifferentiation will be further optimized by modulating regulatory pathways. The success of this research not only will develop a much needed cell therapy to restore sight but also will establish a new model for stem cell therapy in other diseases.
Statement of Benefit to California:
This proposal is to develop a stem cell transplantation therapy for treating a blinding corneal disorder, bilateral limbal stem cell deficiency (LSCD). Because of visual impairment, patients with LSCD lose the ability to drive, read, and watch TV. In addition, they experience recurrent corneal erosion that causes severe pain. Recurrent breakdown of the corneal surface increases the risk of infection that requires frequent medical intervention. All of these factors can have a substantially negative psychological impact on patients and their families. Therefore, LSCD imposes a significant social and economic impact on society. California is the most populated state in the US. More than 36 million people reside in the State of California, and the population is expected to increase to 46 million by 2030. Accordingly, the number of residents with LSCD is likely to increase disproportionately as a result of occupational and environmental risk factors. A new treatment to restore vision would be an important benefit to the people of California. Further, the project would train new stem cell researchers and provide innovation in stem cell therapy. When this project enters the clinical phase, it will bring together new physicians and scientists and attract funding by the federal government and investment from biotechnology companies in California. Stem cell–based transplantation to treat a stem cell–related disease such as LSCD is well aligned with the broad mission of CIRM.
Executive Summary Limbal stem cell deficiency is a significant cause of visual loss in a number of corneal disorders. While autologous limbal stem cell transplants can restore vision in the affected eye, there are a small number of individuals who suffer bilateral limbal stem cell deficiency. The goal of this application is to establish a safe and efficacious source of therapeutic cells for patients suffering from corneal epithelial bilateral limbal stem cell deficiency. The applicant proposes to use autologous human skin epithelial stem cells (SESC) as a cell source for reprogramming to corneal epithelial limbal stem cells. The applicant will optimize SESC isolation then optimize reprogramming through manipulation of a niche modulation of regulatory pathways. Functionality will be evaluated in preclinical model Research Plan - The overall experimental design was weak; some aspects of the proposal were described superficially, lacking crucial details, and some of the science was oversimplified not taking into account complexity of the biology involved. - The approach described in the proposal is not exceptionally novel in that work is underway in other labs exploring alternative cell sources for limbal stem cells, but if successful, it may result in bringing a new therapy to the clinic. - The preliminary data was not particularly strong and much of the data was a repetition of what has been reported in literature. - Each aim is dependent on the previous one and there is no fallback plan should an aim fail. - Reviewers were uncertain of the potential impact of a successful program given the prevalence of bilateral limbal stem cell deficiency or injury. Principle Investigator - While the PI is well published, many of his/her publications are in imaging and lower impact journals. - The PI’s mentors are well-respected translational, stem cell scientists. Institutional commitment - The institutional support for the PI is good. The PI has been provided with lab space to support translational research and has access to excellent facilities in stem cell and clinical research.. - The institute with which the PI is affiliated is well known internationally and has a strong reputation for translational research. Responsiveness - The project fits well within the RFA's objectives and scope.