Induced pluripotent stem cell-based therapy for age-related macular degeneration

Abstract

In age-related macular degeneration (AMD), stem cells could possibly replace or regenerate disrupted pathologic retinal pigment epithelium (RPE), and produce supportive growth factors and cytokines such as brain-derived neurotrophic factor. Induced pluripotent stem cells (iPSCs)-derived RPE was first subretinally transplanted in a neovascular AMD patient in 2014. Areas covered: Induced PSCs are derived from the introduction of transcription factors to adult cells under specific cell culture conditions, followed by differentiation into RPE cells. Induced PSC-derived RPE cells exhibit ion transport, membrane potential, polarized VEGF secretion and gene expression that is similar to native RPE. Despite having similar in vitro function, morphology, immunostaining and microscopic analysis, it remains to be seen if iPSC-derived RPE can replicate the myriad of in vivo functions, including immunomodulatory effects, of native RPE cells. Historically, adjuvant RPE transplantation during CNV resections were technically difficult and complicated by immune rejection. Autologous iPSCs are hypothesized to reduce the risk of immune rejection, but their production is time-consuming and expensive. Alternatively, allogenic transplantation using human leukocyte antigen (HLA)-matched iPSCs, similar to HLA-matched organ transplantation, is currently being investigated. Expert opinion: Challenges to successful transplantation with iPSCs include surgical technique, a pathologic subretinal microenvironment, possible immune rejection, and complications of immunosuppression.

Management of retinitis pigmentosa by Wharton’s jelly derived mesenchymal stem cells: preliminary clinical results

“…In intravitreal and subretinal applications, severe complications have been reported which include proliferative vitreoretinal bands, tractional retinal detachment, exudative retinal detachment etc. [41,[47][48][49][50][51]. Suprachoroidal, subtenon or peribulbar administration methods are not X, mean values obtained from 34 eyes (32 patients); SD standard deviation; %95 CI L and U, 95% confidence interval of the difference (mean) *Bold: Significant p values and related data (i.e., coefficient and standard error) are set in italics Fig.…”

Paracrine effects of intraocularly implanted cells on degenerating retinas in mice

“…However, whether this visual restoration is due to a functional integration of the grafted cells to substitute for lost retinal neurons in recipients or due to their neuroprotective and neurotrophic effects to retain recipient functional neurons, or both, is still under debate. In general, pluripotent stem cells (PSCs), such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), must first be differentiated in vitro into a target cell type, such as photoreceptors (PRs), RPE cells, or retinal ganglion cells (RGCs), prior to transplantation to recipients [1,8]. In contrast, adult stem cells, such as bone marrow-derived stromal cells (BMSCs), adipose stem cells (ASCs), retinal stem cells (RSCs), and umbilical cord stem cells (UCSCs), can be directly grafted to the diseased eyes to remediate their deteriorating vision [1,[9][10][11][12].…”

Stargardt macular dystrophy and evolving therapies

“…Induced pluripotent stem cells (iPSCs) are intriguing in that they can be derived from a previously differentiated cell source and have the potential for reduced ethical controversy over hESC-based therapies, and may negate immunological issues associated with hESC-based therapies. Like with gene therapy, the eye is an ideal candidate for stem cell research because the clear ocular media allows for direct visualization of transplanted cells and the eye is a relatively immune privileged site; furthermore, the size of the eye requires smaller quantities of therapeutic tissue in comparison to other organs [69]. Preclinical studies of hESC-derived RPE cells transplanted into the subretinal space of mouse models of retinal degeneration have been well tolerated and the cells sustained visual function and photoreceptor integrity in a dose-dependent fashion [70,71].…”