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

Abstract

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.

Systemic Injection of RPE65-Programmed Bone Marrow-Derived Cells Prevents Progression of Chronic Retinal Degeneration

“…The poor outcomes have several explanations: (1) the invasive surgery required to prepare the subretinal space; (2) late-stage disease is associated with marked loss of RPE and photoreceptors; (3) a change in myeloid activation and glia activation in the aging retina, or (4) the source of RPE (i.e., advanced donor age) 31, 34. To overcome some of these problems, human embryonic stem cells (hESCs) or induced pluripotent stem cell (iPSC)-derived RPE cells have been used for subretinal transplantation 33, 35, 36. Studies have reported success with both hESC- and iPSC-derived RPE in restoring vision in animal models,35, 36 but although these RPE cell transplants in humans do not result in rejection or hyperproliferation, vision was not greatly enhanced post-transplantation 35 .…”

“…To overcome some of these problems, human embryonic stem cells (hESCs) or induced pluripotent stem cell (iPSC)-derived RPE cells have been used for subretinal transplantation 33, 35, 36. Studies have reported success with both hESC- and iPSC-derived RPE in restoring vision in animal models,35, 36 but although these RPE cell transplants in humans do not result in rejection or hyperproliferation, vision was not greatly enhanced post-transplantation 35 . Although extremely promising, concerns remain regarding genetic stability, and this approach does not overcome the necessity to invade the subretinal space or limitations in disseminating cells across the fundus.…”

Consequences of oxidative stress in age-related macular degeneration

“…A subpopulation of Muller glia with progenitor gene expression have been identified in rodents but there is no definitive evidence that they produce differentiated and functional neurons even though they can express markers for bipolar cells and photoreceptors after injury (Ooto et al, 2004). The clinical approach has been to attempt transplantation of autologous RPE cells or RPE-like cells derived from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPS) (Carr et al, 2009; Du et al, 2011; Lu et al, 2009; Vugler et al, 2007). Human ESC or iPS have the potential to differentiate into rods and cones (Bi et al, 2009; Ikeda et al, 2005; Osakada et al, 2009; Osakada et al, 2007) and can restore light responses when transplanted into the retina of Crx-deficient mice (Lamba et al, 2009a).…”

Visual function 5 years or more after macular translocation surgery for myopic choroidal neovascularisation and age-related macular degeneration

“…To overcome this problem, new therapies such as RPE cell transplantation and transplantation of stem cells are being tried. 3,4 Macular translocation surgery has also been used to treat AMD. In this surgery, the macular area is moved from the underlying damaged RPE to an area of healthier RPE.…”