Degenerative diseases of the retina are cumulatively the most common causes of untreatable blindness. These conditions, which include age-related macular degeneration and retinitis pigmentosa, are characterized by progressive loss of cells in the outer retina. Stem cells hold great promise for treating these diseases by repopulating cells that have been lost. A cell type that will be central to the success of this strategy is the retinal pigment epithelium (RPE). Recent technological breakthroughs make possible for the first time the production of recipient-specific donor cells through reprogramming of pluripotency in adult cells and directed differentiation. However, it is not known how RPE cells produced by these and other methods compare with respect to key biological characteristics, including immunogenicity and mitochondrial senescence, when transplanted to the healthy or diseased retina. These issues are critical to the potential use of such cells for retinal disease therapy. The goal of this proposal is to study the functionality of RPE cells generated from experimentally induced pluripotent stem cells in vitro and after transplantation to the rodent or nonhuman primate retina, including their immunogenicity and their ability to rescue visual loss in a rodent model of retinal degeneration. The project will make innovative use of unique resources, including allograft and autograft stem-cell-derived rhesus monkey RPE cell lines and a naturally-occurring nonhuman primate model of macular disease. The proposal has three specific aims: 1) To generate rhesus macaque RPE cells from three sources of pluripotent stem cells--embryonic stem cells (ESCs), ESCs derived by somatic cell nuclear transfer (SCNT- ESCs), and induced pluripotent stem (iPS) cells--and evaluate their function in arresting visual decline in the RCS retinal degeneration model. 2) To investigate the immunology of these RPE cell types transplanted as allograft or autografts into the retina of adult rhesus monkeys and after retreatment of the same eye or fellow eye. 3) To characterize the differences in immune response between young and senescent rhesus monkeys, including those with age-related maculopathy which parallels intermediate human AMD. This translational research project will provide information key to the success of cell therapy in the retina. It will provide insights as to the most appropriate cell source to repopulate lost retinal cells with the aim of preserving or restoring vision, and will generate novel data on the immune response to such therapeutic intervention and the best approach to avoid graft rejection. The proposal will address these issues in an animal model with an eye and immune system that most closely resembles that of humans and in a manner closely mirroring potential clinical practice.
Retinal degenerative diseases are cumulatively the most frequent causes of blindness in which cells typically in the outer retina (photoreceptors and retinal pigment epithelium) are lost. This proposal focuses on the potential for replacing one such cell type, the retinal pigment epithelium, which can be engineered from various stem cell sources. The ability of these cells to rescue vision will be investigated and we will elucidate the risks of immune rejection. These findings will be key to the safe translation of this therapy into clinic for the treatment of such conditions as age-related macular degeneration.
|McGill, Trevor J; Stoddard, Jonathan; Renner, Lauren M et al. (2018) Allogeneic iPSC-Derived RPE Cell Graft Failure Following Transplantation Into the Subretinal Space in Nonhuman Primates. Invest Ophthalmol Vis Sci 59:1374-1383|
|McGill, Trevor J; Wilson, David J; Stoddard, Jonathan et al. (2018) Cell Transplantation for Retinal Degeneration: Transition from Rodent to Nonhuman Primate Models. Adv Exp Med Biol 1074:641-647|
|Wilson, David J; Neuringer, Martha; Stoddard, Jonathan et al. (2017) SUBRETINAL CELL-BASED THERAPY: An Analysis of Surgical Variables to Increase Cell Survival. Retina 37:2162-2166|
|Izpisua Belmonte, Juan Carlos; Callaway, Edward M; Caddick, Sarah J et al. (2015) Brains, genes, and primates. Neuron 86:617-31|
|Wolf, Don P; Mitalipov, Nargiz; Mitalipov, Shoukhrat (2015) Mitochondrial replacement therapy in reproductive medicine. Trends Mol Med 21:68-76|
|Mitalipov, Shoukhrat; Amato, Paula; Parry, Samuel et al. (2014) Limitations of preimplantation genetic diagnosis for mitochondrial DNA diseases. Cell Rep 7:935-7|
|Kang, Eunju; Wu, Guangming; Ma, Hong et al. (2014) Nuclear reprogramming by interphase cytoplasm of two-cell mouse embryos. Nature 509:101-4|
|Daughtry, Brittany; Mitalipov, Shoukhrat (2014) Concise review: parthenote stem cells for regenerative medicine: genetic, epigenetic, and developmental features. Stem Cells Transl Med 3:290-8|
|Polejaeva, Irina; Mitalipov, Shoukhrat (2013) Stem cell potency and the ability to contribute to chimeric organisms. Reproduction 145:R81-8|
|Tachibana, Masahito; Amato, Paula; Sparman, Michelle et al. (2013) Towards germline gene therapy of inherited mitochondrial diseases. Nature 493:627-31|
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