Funding opportunities

Stem Cell-Derived Retinal Pigment Epithelial cells for Treatment of Age-Related Macular Degeneration and Retinitis Pigmentosa

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
Funds requested: 
$3 096 000
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Age-related macular degeneration (AMD) and Retinitis Pigmentosa (RP) are leading causes of vision loss with no effective cures. Death of Retinal Pigment Epithelium (RPE) in the eye causes AMD and RP. RPE transplantation can restore vision in animals. In people, RPE transplantation has been hindered by lack of healthy human RPE and concerns about whether stem cell derived-RPE are safe to use in patients. Here, we will test which RPE-derived stem cells are safest and healthiest by comparing them with the patient's original RPE. Furthermore, we will generate RPE from a new adult stem cell population, Retinal Pigment Epithelial Stem Cells (RPESCs), present in human eyes. To accomplish these goals, we will take advantage of our unique clinical practice in eye pathology, where we receive 100+ human eyes annually for medical evaluation. We will select healthy human eyes, isolate and characterize RPE and RPESCs, and validate if stem cell-derived RPE can match or even outperform the original RPE, as well as isolate new RPESCs from these eyes. Completion of this project will identify which stem cell-derived RPE is safest for patient use and also result in the creation of a large bank of new human RPESCs that can generate large amounts of healthy functional RPE. These findings will provide fundamental safety data for clinical use of stem cell-derived RPE and also offer new regenerative medicine stem cell resources for patients with AMD or RP.
Statement of Benefit to California: 
Age-related macular degeneration (AMD) and Retinitis Pigmentosa (RP) are devastating diseases of the eye that result in progressive loss of vision. Patients with AMD and RP lose the ability to perform life functions including driving, reading, and watching movies or television. These diseases affect a significant number of people, with over 450,000 Californians predicted to suffer from AMD alone by 2020. These diseases place a significant economic burden on patients by interfering with their economic livelihoods. These diseases cause significant public health and safety burdens by increasing chances that patients will be involved in accidents due to visual impairment. AMD and some types of RP are caused by loss of Retinal Pigment Epithelial (RPE) cells in the eye. Many studies have shown that transplantation of healthy RPE can improve visual function, but it has been difficult to get enough healthy human RPE to develop RPE transplantation into a viable therapy to treat AMD and RP. Here, we propose a stem cell based approach to safely generate large amounts of human RPE based on isolating RPE stem cells from human eyes collected from surgical and autopsy donor enucleations. If successful, our strategy would result in the creation of a large bank of diverse donor RPE stem cells whose functional, genetic, and molecular phenotypes would be characterized and then, provided as a new stem cell-based resource for vision restoration therapy in patients with AMD or RP.
Review Summary: 
Executive Summary Age-related macular degeneration (AMD) and Retinitis Pigmentosa (RP) are leading causes of visual loss in the elderly, both resulting from the death of retinal pigment epithelium (RPE) cells in the retina. One possible treatment for these diseases is transplantation of stem cell-derived RPE cells into the eye. To help validate the safety of this approach, this study aims to molecularly and functionally compare patient-matched induced pluripotent stem cell (iPSC) derived RPE cells with primary RPE cells isolated from human eyes (Aim 1). In addition, the Principle Investigator (PI) will test the ability of stem cell-derived RPEs to mount specific cellular responses and survive cellular stresses (Aim 2). Finally, in Aim 3, the PI proposes to characterize and compare RPE and RPE stem cells (RPESCs) from different patient demographic groups and generate a bank of RPESC that may be used in the future as a resource for stem cell-based vision therapy for AMD or RP patients. Research Plan - There is little novel about the proposed study and the impact is likely to be small. RPE transplantation of hESC/iPSC-derived RPE cells has reached Phase1/2 clinical trials with no reported contraindications and some evidence of visual improvement. - A rationale presented to justify Aim 1 of this proposal is that there may be safety questions about using stem cell-derived RPE cells for transplantation. However, this question has already been extensively analyzed and such stem cell-derived RPE are being used in a number of clinical trials. Thus it is unclear what additional information this part of the study will provide. - - It is unclear how the Aim 1 molecular comparisons between iPSC-derived RPE with primary RPE from the patient could be interpreted from the safety standpoint or would identify inherent differences. Molecular differences are to be expected simply because the former are rejuvenated whereas the latter have undergone changes during the patient’s life. Furthermore, it isn’t clear that the sample sizes proposed are large enough to lend statistical power to the study. - The rodent model proposed to test RPE function in vivo is not useful for detecting differences between cell sources of RPE since almost any cell type can rescue vision in this model. Some preliminary data is provided but much of this is simply repetition of isolation and differentiation procedures reported by others. - The strengths in the second aim are are the comparison between AMD and non-AMD patients and the PI's expertise in the cellular stress - Aim 3 will attempt to isolate a newly identified cell type (RPESC) with which the PI and mentor have no experience. The rationale for this aim is weak and the aim is poorly developed. However, despite the limitations some reviewers found this was probably the most original part of the study. Principal Investigator - The PI has a strong track record as an independent physician scientist and ophthalmic pathologist. She/he has a good publication record. - RPE cell biology and stem cells appear to be a completely new field for the PI. - The applicant’s mentor is a well-established internationally known clinician scientist and would be an excellent career mentor for the PI. However, reviewers commented that it would be advantageous to add an additional mentor in the field of RPE stem cell biology to the mentoring plan. - The PI has the potential to become an established physician scientist in vision sciences but reviewers were not convinced from the information provided that this will necessarily be in RPE stem cell biology. - The PI presents a comprehensive career development plan with detailed milestones for translating his/her research into proven clinical therapies. Institutional Commitment - The Institution has made a major commitment to the PIs career development as a physician scientist. The PI was provided with laboratory space, administrative infrastructure, start up funds and has access to all core facilities at his/her institution including the Human Embryonic Stem Cell Core Facility. Responsiveness - This application is responsive to the RFA in that it will characterize and compare RPE cells derived from different stem cell sources, with the aim of determining the best source for clinical translation.
Programmatic review: 
  • A motion was made to move this application into Tier 1, Recommended for Funding, since AMD is an important problem to cure. However, it was noted that CIRM has already funded proposals in this area that are at a more advanced stage and in addition to that, significant progress is being made elsewhere in the world as well. The motion failed.

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