$4 880 116
The long term goal of our research program is regeneration of the diseased eye. Age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa are leading causes of blindness for which there are no effective treatments for the majority of cases. Loss of vision is due to progressive degeneration of the photoreceptor cells, or loss of cells that support the photoreceptors, such as retinal pigment epithelial (RPE) cells or cells in the retinal blood vessels. The RPE is a pigmented cell layer that lies just behind the retinal and is necessary for photoreceptor survival. One possible strategy for treatment of these blinding diseases is to replace cells that are lost via transplantation. My work explores this approach, with the object of first identifying and characterizing sources of cells, determining the optimal parameters for transplantation, and investigating molecular, cellular and behavioral events that occur upon transplantation in animal models of retinal degeneration. In the case of age-related macular degeneration, there is a solid body of evidence that RPE cell loss is often an early event in disease progression. We have shown that RPE can be derived from human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC), and they can rescue vision in rodent and pig models of retinal dystrophy. We have joined forces with interdisciplinary teams in the UK and California to transition this work to the clinic, using RPE derived from hESC. We will also investigate other forms of RPE-based eye disease by generating iPSC from patients, differentiating them to RPE, and analyzing function. Small molecules that are candidate drugs will then be screened for functional rescue. In the case of diabetic retinopathy, we are investigating a strategy to used hESC-derived cells to repair blood vessels. Finally, in retinitis pigmentosa, we will pursue a possible route to replace photoreceptors by converting the surviving retinal ganglion cells into light sensing cells. The aim of the proposed studies is to provide foundational knowledge that will enable and guide further translation of cellular therapies to improve vision in patients.
Statement of Benefit to California:
Age-related macular degeneration (AMD), retinitis pigmentosa (RP) and diabetic retinopathy are leading causes of vision loss and blindness. Because California is the most populous state in the nation, and because the elderly constitute a greater percentage of its population, it is estimated that over 450,000 of Californians will suffer from AMD with severe vision impairment by 2020, leading to huge costs. Diabetes continues to be a major health concern, with vision loss a common outcome. Moreover, the devastating consequences of vision deficits include the progressive loss of independence and productivity, and increased risks of falls, fractures, and depression among diseased population. So this is not only a problem of the individual quality of life, but also an issue of increasing public health burden and concern. Clearly, there is a need for better treatments. In these diseases, loss of vision is due to progressive degeneration of the light sensitive photoreceptor cells of the eye or defects in the supporting cells of the eye, including the retinal pigmented epithelium (RPE). There is now a solid body of evidence that suggests that RPE degeneration is the first step in AMD. There is no cure for these conditions at present, although studies of model experimental animals, mostly rats and mice, suggest several possible routes to therapy. One of these involves the transplantation of cells to slow the degeneration of photoreceptors by replacing key support cells lost during degeneration. My work explores this approach with the object of first identifying and characterizing sources of ocular cells, determining the optimal parameters for transplantation, and identifying molecular and cellular and behavioral events that occur upon transplantation in animal models of retinal degeneration. One source of cells for transplantation is ocular cells derived from human embryonic stem cells (hESC) or induced pluripotent stem cells (iPSC). We have shown that ocular cells, especially RPE, can be derived from both hESC and iPSC, and they can rescue visual function in rodent models of retinal dystrophy. We have shown that RPE can be derived from both hESC and iPSC, and they can rescue visual function in rodent models of retinal dystrophy. We have teamed up with an interdisciplinary disease team of stem cell biologists, materials chemists, neuroscientists, and retinal surgeons to transition this work towards clinical application for AMD, using hESC to produce RPE. Other research aims are to generate specific blood vessel cells from stem cells to replenish the retinal blood vessels in diabetic retinopathy, to generate new photosensitive cells to restore vision, and to use iPSC derived from patients to understand retinal disease and identify novel treatments. California patients with vision loss will benefit greatly from the studies proposed.
The candidate principal investigator (PI) is a mid-career neuroscientist who directs an active and collaborative research program at an academic institution. The PI’s research focuses on studies of retinal cells and retinal repair. Ongoing research projects address the use of stem cells for the treatment of age-related macular degeneration (AMD) and other diseases of retinal degeneration. Aims of the proposed research include the development of cell transplantation therapies using animal models and activities progressing to human clinical trials, the further study of retinal diseases and development of bioassays for the characterization of molecular targets using induced pluripotent stem cells (iPSC) derived from affected individuals, and the development of novel strategies for the rescue of functional, surviving retinal tissue in particular disease models. These approaches should substantially advance the field toward treatments for retinal pathologies and blinding diseases. Reviewers characterized the PI’s research vision and plans as truly innovative, novel, ambitious, and important. The research focus on devastating and currently incurable blinding diseases was viewed as highly significant, with a potential to revolutionize the field. Reviewers were confident that the PI’s research would contribute to both the critical basic science and preclinical advances that will underlie novel therapies. The PI was recognized as an outstanding investigator and emerging leader in stem cell research directed at ophthalmic diseases. He/she has demonstrated substantial research productivity, with significant numbers of publications in high-impact journals; many of these publications have helped shape the field of translational research in retinal pathology. These contributions have been recognized by numerous invitations to present work and by several awards. The PI has demonstrated leadership both within his/her institution and in the broader scientific field of translational vision research. The PI was praised in letters from leaders in both stem cell biology and the field of ophthalmic disease who emphasized the candidate’s excellent record of achievement and pioneering contributions to cell transplantation. The PI was further lauded for his/her talent in assembling interdisciplinary research teams and engaging in productive collaborations. Reviewers viewed the institutional commitment as strong and likely to provide resources and an environment highly supportive of the PI’s research. This commitment includes personnel resources, laboratory space, research support services and substantial funding for equipment and laboratory renovation. The institution possesses significant strength in vision research and a fertile environment for collaborative projects, and the PI’s recruitment would build upon this foundation and enhance program initiatives in stem cell biology and translational activities. In summary, this is a strong application from an emerging leader in vision research and stem cell-based approaches to treating retinal disease. Particular strengths include the PI’s productivity and achievements, a highly innovative and ambitious research plan, a strong institutional commitment, and a supportive, collaborative institutional environment for stem cell research and translation that will be further strengthened by the candidate’s successful recruitment.