Development of a Stem Cell-based Transplantation Strategy for Treating Age-related Macular Degeneration
Early Translational I
$5 503 069
Statement of Benefit to California:
This proposal focuses on the development of novel cell therapies for the treatment of age-related macular degeneration (AMD). AMD is a common blinding disease of the elderly caused by progressive accumulation of degenerative and vascular changes in the macula of the eye, particularly in the retinal pigment epithelium (RPE). The applicant proposes a cell replacement therapy in which RPE cells would be transplanted into the subretinal space of the patient’s eye. First, the applicant proposes to differentiate RPE cells from two autologous stem cells sources: ciliary margin zone (CMZ) cells obtained by biopsy of the eye, and induced pluripotent stem cells (iPSCs) from skin fibroblasts. The applicant will test these cells for function first in vitro and then in vivo by transplantation into several transgenic mouse models of eye disease. To address the pathophysiology of AMD in which inflammation is believed to be due to inappropriate attack of RPE cells by the complement system, the applicant proposes to test stem cell-derived RPE cells that have been genetically modified to overexpress negative regulators of the complement cascade. Finally, the applicant will monitor the potential tumorigenicity of iPSC-derived RPE cells by transplantation into immunodeficient mice. The reviewers agreed that this proposal addresses an unmet medical need and could have significant impact. They noted that AMD is a common and severe disease lacking effective therapies and an attractive target for stem cell derived therapies. The eye confers several advantages as a transplantation site, including the ability to monitor transplanted cells non-invasively and the option of removing an eye in the event of tumorigenesis (to prevent life threatening spread). A reviewer noted that surgical methods exist for the replacement of diseased RPE but allogeneic transplanted RPE eventually undergo immune rejection. This proposal circumvents this issue by using autologous cell sources to derive RPE cells. Several forms of autologous transplantation therapies for AMD have generated encouraging results, including macular translocation, iris pigment epithelial cell transplant and peripheral retinal RPE cell transplant. But all of these methods have limitations in either cell functionality or the number of cells available for collection and transplantation. This proposal addresses those limitations by using a potentially unlimited source of autologous cells (iPSCs) and several strategies for functional testing and optimization. The reviewers described the research plan as well laid-out and carefully designed. They found the proposal to be feasible and praised the preliminary data showing differentiation and in vitro characterization of RPE cells. Some concerns were expressed about the lack of data describing transduction of RPEs with the viral vectors, whether replenishment of RPEs will be therapeutic for AMD, and whether transplanted cells will suffer the same fate as the original cells. However, reviewers agreed that the assays for RPE function are well described and praised the elegant use of in vitro and in vivo functional tests. Reviewers appreciated the applicant’s appropriate consideration of the need for immune modulation and the risk of tumorigenesis but expressed some concern about the validity of the mouse model for preclinical assessment and cautioned about issues surrounding xenotransplantation in the immune modulation experiments. The reviewers praised the qualifications of the applicant and assembled research team. One reviewer noted that the team is particularly strong in RPE physiology and assays of visual function. Although the team lacks extensive experience in stem cell biology, a core facility is readily available to supply expertise and help in the generation of clinical-grade cells. Reviewers raised significant concerns with the budget, finding it excessive in the number of FTEs, supplies, requested equipment purchases, and travel. Reviewers noted that the available resources and research environment for the proposed studies are excellent. Overall, reviewers were highly enthusiastic about the potential impact of the proposed research and felt that AMD represents one of the best opportunities for advancing stem cell-based therapies to the clinic. Reviewers praised the careful, logical design of the research plan and were optimistic about its feasibility based on impressive and relevant preliminary data.