Induced Pluripotent Stem Cell Therapies for Geographic Atrophy of Age-Related Macular Degeneration

Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, CA 92093, USA.
Seminars in ophthalmology (Impact Factor: 0.86). 05/2011; 26(3):216-24. DOI: 10.3109/08820538.2011.577498
Source: PubMed


There is currently no FDA-approved therapy for treating patients with geographic atrophy (GA), a late stage of age-related macular degeneration (AMD). Cell transplantation has the potential to restore vision in these patients. This review discusses how recent advancement in induced pluripotent stem (iPS) cells provides a promising therapy for GA treatment. Recent advances in stem cell biology have demonstrated that it is possible to derive iPS cells from human somatic cells by introducing reprogramming factors. Human retinal pigment epithelium (RPE) cells and photoreceptors can be derived from iPS cells by defined factors. Studies show that transplanting these cells can stabilize or recover vision in animal models. However, cell derivation protocols and transplantation procedures still need to be optimized. Much validation has to be done before clinical-grade, patient-derived iPS can be applied for human therapy. For now, RPE cells and photoreceptors derived from patient-specific iPS cells can serve as a valuable tool in elucidating the mechanism of pathogenesis and drug discovery for GA.

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    • "In vitro modelling of hiPSC-derived RPE cells has been a focus of research in ophthalmic research. Access to renewable sources of highly functional and expandable human RPE is ideal for studying these cells and the diseases affecting them (Du et al. 2011; Singh et al. 2013b). Different protocols for the differentiation of human pluripotent stem cells (hPSCs) into RPE have been described. "
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    ABSTRACT: Induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) has widely been appreciated as a promising tool to model human ocular disease emanating from primary RPE pathology. Here, we describe the successful reprogramming of adult human dermal fibroblasts to iPSCs and their differentiation to pure expandable RPE cells with structural and functional features characteristic for native RPE. Fibroblast cultures were established from skin biopsy material and subsequently reprogrammed following polycistronic lentiviral transduction with OCT4, SOX2, KLF4 and L-Myc. Fibroblast-derived iPSCs showed typical morphology, chromosomal integrity and a distinctive stem cell marker profile. Subsequent differentiation resulted in expandable pigmented hexagonal RPE cells. The cells revealed stable RNA expression of mature RPE markers RPE65, RLBP and BEST1. Immunolabelling verified localisation of BEST1 at the basolateral plasma membrane, and scanning electron microscopy showed typical microvilli at the apical side of iPSC-derived RPE cells. Transepithelial resistance was maintained at high levels during cell culture indicating functional formation of tight junctions. Secretion capacity was demonstrated for VEGF-A. Feeding of porcine photoreceptor outer segments revealed the proper ability of these cells for phagocytosis. IPSC-derived RPE cells largely maintained these properties after cryopreservation. Together, our study underlines that adult dermal fibroblasts can serve as a valuable resource for iPSC-derived RPE with characteristics highly reminiscent of true RPE cells. This will allow its broad application to establish cellular models for RPE-related human diseases. Electronic supplementary material The online version of this article (doi:10.1007/s12017-014-8308-8) contains supplementary material, which is available to authorized users.
    Neuromolecular medicine 05/2014; 16(3). DOI:10.1007/s12017-014-8308-8 · 3.68 Impact Factor
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    • "Stem cell biology can offer profound insight into the mechanisms of AMD [19] and can provide new approaches for autologous cell-based therapy in AMD as supported by the recently FDA approved clinical trial (NCT01344993). Generation of RPE derived from patient-specific induced pluripotent stem (iPS) cells may offer the ability to recapitulate the disease state and screen new therapeutics, improving upon the limited treatment strategies currently available to afflicted patients. "
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    ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of blindness in people over age 55 in the U.S. and the developed world. This condition leads to the progressive impairment of central visual acuity. There are significant limitations in the understanding of disease progression in AMD as well as a lack of effective methods of treatment. Lately, there has been considerable enthusiasm for application of stem cell biology for both disease modeling and therapeutic application. Human embryonic stem cells and induced pluripotent stem cells (iPSCs) have been used in cell culture assays and in vivo animal models. Recently a clinical trial was approved by FDA to investigate the safety and efficacy of the human embryonic stem cell-derived retinal pigment epithelium (RPE) transplantation in sub-retinal space of patients with dry AMD These studies suggest that stem cell research may provide both insight regarding disease development and progression, as well as direction for therapeutic innovation for the millions of patients afflicted with AMD.
    Journal of Translational Medicine 03/2013; 11(1):53. DOI:10.1186/1479-5876-11-53 · 3.93 Impact Factor
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    • "Replacing defective RPE cells has been proposed as a mechanism to ameliorate both neovascular(Tezel, et al., 2007) and atrophic(Du, et al., 2011) AMD. Elegant experiments at delivering RPE cells from a variety of potential sources(da Cruz, et al., 2007) indicate that modifying BrM to accept transplanted cells(Gullapalli, et al., 2004) and/or delivering cells on degradable scaffolds(Thomson, et al., 2010) will be necessary for successful transplantation. "
    Age Related Macular Degeneration - The Recent Advances in Basic Research and Clinical Care, 01/2012; , ISBN: 978-953-307-864-9
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