Treatment Of Retinal Degenerative Diseases Research Articles

Vitamin C- and Valproic Acid-Induced Fetal RPE Stem-like Cells Recover Retinal Degeneration via Regulating SOX2

Retinal pigment epithelial (RPE) cell replacement therapy has provided promising outcomes in the treatment of retinal degenerative diseases (RDDs), but the resulting limited visual improvement has raised questions about graft survival and differentiation. Through combined treatment with vitamin C and valproic acid (together, VV), we activated human fetal RPE (fRPE) cells to become highly proliferative fetal RPE stem-like cells (fRPESCs). In this study, we report that SOX2 (SRY-box 2) activation contributed to mesenchymal-epithelial transition and elevated the retinal progenitor and mesenchymal stromal markers expressions of fRPESCs. These fRPESCs could differentiate into RPE cells, rod photoreceptors, and mesenchymal lineage progenies under defined conditions. Finally, fRPESCs were transplanted into the subretinal space of an RDD mouse model, and a photoreceptor rescue benefit was demonstrated. The RPE and rod photoreceptor differentiation of transplanted fRPESCs may account for the neural retinal recovery. This study establishes fRPESCs as a highly proliferative, multi-lineage differentiation potential (including RPE, rod photoreceptor, and mesenchymal lineage differentiation), mesenchymal-to-epithelial-transitioned retinal stem-like cell source for cell-based therapy of RDDs.

Endoplasmic reticulum stress: New insights into the pathogenesis and treatment of retinal degenerative diseases.

Physiological equilibrium in the retina depends on coordinated work between rod and cone photoreceptors and can be compromised by the expression of mutant proteins leading to inherited retinal degeneration (IRD). IRD is a diverse group of retinal dystrophies with multifaceted molecular mechanisms that are not fully understood. In this review, we focus on the contribution of chronically activated unfolded protein response (UPR) to inherited retinal pathogenesis, placing special emphasis on studies employing genetically modified animal models. As constitutively active UPR in degenerating retinas may activate pro-apoptotic programs associated with oxidative stress, pro-inflammatory signaling, dysfunctional autophagy, free cytosolic Ca2+ overload, and altered protein synthesis rate in the retina, we focus on the regulatory mechanisms of translational attenuation and approaches to overcoming translational attenuation in degenerating retinas. We also discuss current research on the role of the UPR mediator PERK and its downstream targets in degenerating retinas and highlight the therapeutic benefits of reprogramming PERK signaling in preclinical animal models of IRD. Finally, we describe pharmacological approaches targeting UPR in ocular diseases and consider their potential applications to IRD.

KIT ligand protects against both light-induced and genetic photoreceptor degeneration.

Photoreceptor degeneration is a major cause of blindness and a considerable health burden during aging but effective therapeutic or preventive strategies have not so far become readily available. Here, we show in mouse models that signaling through the tyrosine kinase receptor KIT protects photoreceptor cells against both light-induced and inherited retinal degeneration. Upon light damage, photoreceptor cells upregulate Kit ligand (KITL) and activate KIT signaling, which in turn induces nuclear accumulation of the transcription factor NRF2 and stimulates the expression of the antioxidant gene Hmox1. Conversely, a viable Kit mutation promotes light-induced photoreceptor damage, which is reversed by experimental expression of Hmox1. Furthermore, overexpression of KITL from a viral AAV8 vector prevents photoreceptor cell death and partially restores retinal function after light damage or in genetic models of human retinitis pigmentosa. Hence, application of KITL may provide a novel therapeutic avenue for prevention or treatment of retinal degenerative diseases.

Flavonoid supplements increase neurotrophin activity to modulate inflammation in retinal genetic diseases.

Retinal degenerative disorders induce loss of photoreceptors associated with inflammation, and negative remodeling and plasticity of neural retina. Retinal degenerative diseases may have genetic and/or environmental causes. Degeneration of retinal pigment epithelium cells initiates a vicious circle increasing the ongoing inflammation in both retina and choroid. Flavonoids are polyphenolic molecules with antioxidant activity and dietary intake, specifically of anthocyanins and flavanols, improves oxidative stress and neuro-inflammation. In vitro and ex vivo studies have also revealed biological effects of flavonoids on retinal protection against oxidative stress and inflammation. In this brief review, the protective role of flavonoids against retinal degeneration and inflammation will be discussed along with their therapeutic potential for the treatment of retinal degenerative diseases. (www.actabiomedica.it)

The Application of Methylprednisolone Nanoscale Zirconium-Porphyrin Metal-Organic Framework (MPS-NPMOF) in the Treatment of Photoreceptor Degeneration.

BackgroundPhotoreceptor degeneration is one of the most refractory oculopathy in the world, leading to vision loss in severe cases. Methyprednisolone is one of the most commonly prescribed medications for the treatment of retinal degenerative diseases, either by oral administration or repeated intraocular injections. However, the efficacy was unsatisfactory due to its systemic or local side effects and short retention time within the retina.MethodsNanoscale zirconium-porphyrin metal-organic framework (NPMOF) was synthesized and characterized. The biotoxicity and imaging capability of NPMOF were evaluated using zebrafish embryos and larvae. NPMOF was then used as a skeleton and loaded with methylprednisolone (MPS) to prepare a novel kind of nanoparticle, MPS-NPMOF. Photoreceptor degeneration was induced by high-intensity light exposure in adult zebrafish. MPS-NPMOF was delivered to the injured retina by intraocular injection. The photoreceptor regeneration and its underlying mechanism were explored by immunohistochemistry, quantitative real-time polymerase chain reaction and behavioral test.ResultsNPMOF not only had low biotoxicity but also emitted bright fluorescence. Following a single MPS-NPMOF intraocular injection, the injured retina exhibited the faster photoreceptor regeneration with better visual function by promoting the cell proliferation.ConclusionNPMOF is an ideal carrier and could be applied in tracking and delivering medications. By intraocular injection, the novel drug delivery system, MPS-NPMOF, accomplishes the sustained release of drug and plays a therapeutic role in photoreceptor degeneration.

Hif1a and Hif2a can be safely inactivated in cone photoreceptors

Impaired tissue oxygenation results in hypoxia and leads to the activation of hypoxia-inducible transcription factors (HIF). A chronic, HIF-triggered molecular response to hypoxia may be an important factor in the etiology of age-related macular degeneration (AMD) and is likely activated before any clinical manifestation of the disease. Thus, HIF1 and HIF2 recently emerged as potential therapeutic targets for AMD. To address and evaluate potential consequences of anti-HIF therapies for retinal physiology and function, we generated mouse lines that have Hif1a, or both Hif1a and Hif2a ablated specifically in cone photoreceptors. The knockdown of Hifs in cones did not cause detectable pathological alterations such as loss of cone photoreceptors, retinal degeneration or abnormalities of the retinal vasculature, had no impact on retinal function and resulted in a similar tolerance to hypoxic exposure. Our data indicate that HIF transcription factors are dispensable for maintaining normal cone function and survival in retinas of adult mice. This study provides the groundwork necessary to establish safety profiles for strategies aiming at antagonizing HIF1A and HIF2A function in cone photoreceptors for the treatment of retinal degenerative diseases that involve a hypoxic component such as AMD.

Restoration of visual function by transplantation of optogenetically engineered photoreceptors

A major challenge in the treatment of retinal degenerative diseases, with the transplantation of replacement photoreceptors, is the difficulty in inducing the grafted cells to grow and maintain light sensitive outer segments in the host retina, which depends on proper interaction with the underlying retinal pigment epithelium (RPE). Here, for an RPE-independent treatment approach, we introduce a hyperpolarizing microbial opsin into photoreceptor precursors from newborn mice, and transplant them into blind mice lacking the photoreceptor layer. These optogenetically-transformed photoreceptors are light responsive and their transplantation leads to the recovery of visual function, as shown by ganglion cell recordings and behavioral tests. Subsequently, we generate cone photoreceptors from human induced pluripotent stem cells, expressing the chloride pump Jaws. After transplantation into blind mice, we observe light-driven responses at the photoreceptor and ganglion cell levels. These results demonstrate that structural and functional retinal repair is possible by combining stem cell therapy and optogenetics.

Retinal stem cell transplantation: Balancing safety and potential.

Stem cell transplantation holds great promise as a potential treatment for currently incurable retinal degenerative diseases that cause poor vision and blindness. Recently, safety data have emerged from several Phase I/II clinical trials of retinal stem cell transplantation. These clinical trials, usually run in partnership with academic institutions, are based on sound preclinical studies and are focused on patient safety. However, reports of serious adverse events arising from cell therapy in other poorly regulated centers have now emerged in the lay and scientific press. While progress in stem cell research for blindness has been greeted with great enthusiasm by patients, scientists, doctors and industry alike, these adverse events have raised concerns about the safety of retinal stem cell transplantation and whether patients are truly protected from undue harm. The aim of this review is to summarize and appraise the safety of human retinal stem cell transplantation in the context of its potential to be developed into an effective treatment for retinal degenerative diseases.

Genetically-modified human mesenchymal stem cells to express erythropoietin enhances differentiation into retinal photoreceptors: An in-vitro study

Dysfunctional or death of retinal photoreceptors is an irreversible phenomenon that is closely associated with a broad range of retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration (AMD), resulting in successive loss of visual function and blindness. In search for viable treatment for retinal degenerative diseases, mesenchymal stem cells (MSCs) has demonstrated promising therapeutic capabilities to repair and replace damaged photoreceptor cells in both in vitro and in vivo conditions. Nevertheless, the dearth of MSC differentiation capacity into photoreceptors has limited its use in cell replacement therapy. Erythropoietin (EPO) has vital role in early neural retinal cell differentiation and demonstrated rescue potential on dying photoreceptor cells. Hence, we aimed to evaluate the differentiation capacity of MSCs into photoreceptor cells in the presence of human EPO protein. We derived the MSC from human Wharton's jelly of umbilical cord and transduced the cells with lentivirus particles encoding EPO and green fluorescent protein (GFP) as reporter gene. The transduced cells were selectively cultured and induced to differentiate into photoreceptors by exposing to photoreceptor differentiation cocktail. Our preliminary results showed that transduced cells exposed to induction medium had an enhanced differentiation capacity when compared to non-transduced cells. Our results demonstrated a novel strategy to increase the yield of in vitro photoreceptor differentiation and may be potentially useful in improving the efficiency of stem cell transplantation for ocular disorders.

Gene and Induced Pluripotent Stem Cell Therapy for Retinal Diseases.

Given the importance of visual information to many daily activities, retinal degenerative diseases-which include both inherited conditions (such as retinitis pigmentosa) and acquired conditions (such as age-related macular degeneration)-can have a dramatic impact on human lives. The therapeutic options for these diseases remain limited. Since the discovery of the first causal gene for retinitis pigmentosa almost three decades ago, more than 250 genes have been identified, and gene therapies have been rapidly developed. Simultaneously, stem cell technologies such as induced pluripotent stem cell-based transplantation have advanced and have been applied to the treatment of retinal degenerative diseases. Here, we review recent progress in these expanding fields and discuss the potential for precision medicine in ophthalmic care.

Inhibition of miR‐144‐3p enhances Nrf2 and protects against retinal degeneration

Retinal pigment epithelial (RPE) cells are consistently exposed to high levels of pro‐oxidant and inflammatory stimulation. As such under normal conditions, the antioxidant machinery in this cell type is one of the most efficient in the entire body. In aging and disease however, these defense mechanisms often fail, leaving RPE susceptible to damage, which contributes, to degeneration of the outer retina. Thus, understanding better the mechanisms that regulate antioxidant responses is critically important. Oxidative stress increases the expression of several miRNAs, known as oxidative stress‐responsive miRNAs however, the mechanisms by which these miRs regulate expression of antioxidant target genes and related signaling is not completely understood. In the present study, we evaluated the role of the redox sensitive microRNA, miR‐144‐3p, in antioxidant signaling in RPE cells. In our cell culture model system, miR‐144‐3p expression was up‐regulated in response to pro‐oxidant stimuli. Over‐expression of miR‐144‐3p attenuated expression of Nrf2 and related antioxidant genes thereby increasing the susceptibility of RPE cells to further oxidative damage. Thus, we hypothesized that inhibiting miR‐144‐3p might be protective against RPE/retinal damage. To test this, 8‐wk old male C57BL/6J mice were treated with single dose of 50 mg/kg sodium iodate (i.p.) to induce retinal degeneration. However, sub‐retinal injection of miR‐144‐3p antagomir (5μg/kg) preserved retinal integrity, decreased oxidative stress, limited apoptosis and enhanced the expression of antioxidant genes in this mouse model of retinal degeneration. Our present study establishes inhibition of miR‐144‐3p as a potential therapeutic target for prevention and treatment of degenerative retinal diseases in which RPE is prominently affected.Support or Funding InformationThis study was supported by NIH Grant EY022704.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Persistent Activation of STAT3 Pathway in theRetina Induced Vision Impairment and Retinal Degenerative Changes in Ageing Mice.

Neurotrophic factors can promote the survival of degenerating retinal cells through the activation of STAT3 pathway. Thus, augmenting STAT3 activation in the retina has been proposed as potential therapy for retinal dystrophies. On the other hand, aberrant activation of STAT3 pathway is oncogenic and implicated in diverse human diseases. Furthermore, the STAT3/SOCS3 axis has been shown to induce the degradation of rhodopsin during retinal inflammation. In this study, we generated and used mice with constitutive activation of STAT3 pathway in the retina to evaluate the safety and consequences of enhancing STAT3 activities in the retina as a potential treatment for retinal degenerative diseases. We show that long-term activation of the STAT3 pathway can induce retinal degenerative changes and also exacerbate uveitis and other intraocular inflammatory diseases. Mechanisms underlying the development of vision impairment in the STAT3c-Tg mice derived in part from STAT3-mediated inhibition of rhodopsin and overexpression of SOCS3 in the retina. These results suggest that much caution should be exercised in the use of STAT3 augmentation therapy for retinal dystrophies.

An optimized protocol for generating labeled and transplantable photoreceptor precursors from human embryonic stem cells

Cell replacement therapy is a promising approach for treatment of retinal degenerative diseases. Several protocols for the generation of photoreceptor precursors (PRP) from human embryonic stem cells (hESC) have been reported with variable efficiency. Herein, we show the advantages of use of size-controlled embryoid bodies in the ESC differentiation process using two differentiation protocols. We further explored cell-labeling methods for following the survival of PRP transplanted subretinally in rat eyes. Size-controlled embryoid bodies (EBs) generated using microwell dishes and non-size-controlled EBs generated using V-shaped 96-well plates were differentiated into PRP using two differentiation protocols. The differentiation protocols utilized two different combinations of growth factors. The first, Dkk1, Noggin, and IGF1, and the second protocol used IWR1e, SAG, and CHIR99021. Differentiation efficiency to PRP was analyzed by qPCR, immunocytochemistry, and fluorescence-assisted cell sorting (FACS). Size-controlled IWR1e yielded a significantly higher percent (86.4%) of PRP cells expressing CRX, compared with non-size-controlled IWR1e (51.4%, P = 0.026) or the size-controlled DKK1 protocol (70.5%, p = 0.007). In addition, the IWR1e differentiated cells exhibited a significantly higher fluorescence intensity of CRX immunostaining, compared with the DKK1 protocol, consistent with higher protein expression levels. The IWR1e cells exhibited higher maturation levels, as manifested by lower early neuronal marker PAX6 and pluripotency marker OCT4 levels compared with the DKK1 protocol. The expression of other late photoreceptor markers (NRL, recoverin) were similar among the differentiation groups.PRP cells were labeled by using hESC constitutively expressing EGFP or by AAV-GFP transduction. Finally, we transplanted the cells in the subretinal space of wild-type rats and monitored their survival over several weeks. The AAV2 serotype efficiently transduced the PRP cells, whereas other serotypes yielded low or no transduction. Following subretinal transplantation of GFP-labeled PRP, 63% of the cells were detected at 4 weeks post-transplantation. In conclusion, we show here that the IWR1e protocol using size-controlled EBs efficiently generated of PRP that could be labeled and followed in-vivo for weeks. The data from this study is an advance toward the goal of PRP transplantation therapy for retinal degenerative diseases.

Application of CRISPR/Cas9 technologies combined with iPSCs in the study and treatment of retinal degenerative diseases.

Retinal degeneration diseases, such as age-related macular degeneration and retinitis pigmentosa, affect millions of people worldwide and are major causes of irreversible blindness. Effective treatments for retinal degeneration, including drug therapy, gene augmentation or transplantation approaches, have been widely investigated. Nevertheless, more research should be dedicated to therapeutic methods to improve future clinical treatments. Recently, with the rapid development of genome-editing technology, gene therapy has become a potentially effective treatment for retinal degeneration diseases. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has been developed as a powerful genome-editing tool in ophthalmic studies. The CRISPR/Cas9 system has been widely applied in basic research to develop animal models and gene therapies in vivo. With the ability to self-renew and the potential to differentiate into different types of cells, induced pluripotent stem cells (iPSCs) have already been used as a promising tool for understanding disease pathophysiology and evaluating the effect of drug and gene therapeutics. iPSCs are also a cell source for autologous transplantation. In this review, we compared genome-editing strategies and highlighted the advantages and concerns of the CRISPR/Cas9 system. Moreover, the latest progress and applications of the CRISPR/Cas9 system and its combination with iPSCs for the treatment of retinal degenerative diseases are summarized.

Paeoniflorin attenuates atRAL-induced oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress in retinal pigment epithelial cells via triggering Ca2+/CaMKII-dependent activation of AMPK.

Abnormal accumulation of the free-form all-trans-retinal (atRAL), a major intermediate of human visual cycle, is considered to be a key cause of retinal pigment epithelial (RPE) dysfunction in the pathogenesis of retinal degenerative diseases such as age-related macular degeneration (AMD). Paeoniflorin (PF), a monoterpene glucoside isolated from Paeonia lactiflora Pall., has been used in clinical treatment of retinal degenerative diseases in China for several years; however, the underlying mechanism remains unclear. The aim of this study is to investigate the protective effect of PF against atRAL toxicity in human ARPE-19 cells and its molecular mechanism. The results of our study showed that the pre-treatment of PF dose-dependently attenuated atRAL-induced cell injury by the reduction of Nox1/ROS-associated oxidative stress, mitochondrial dysfunction and GRP78-PERK-eIF2α-ATF4-CHOP-regulated endoplasmic reticulum (ER) stress in ARPE-19 cells. Additionally, our data showed that PF mainly exerted its activity via triggering calcium-calmodulin dependent protein kinase II (CaMKII)-mediated activation of AMP-activated protein kinase (AMPK). AMPK inhibition significantly reversed the protective effect of PF against atRAL toxicity in ARPE-19 cells. Overall, our findings provided the novel mechanism of PF protecting human RPE cells, which may prevent the progression of retinal degenerative diseases.

Resveratrol Modulates SIRT1 and DNMT Functions and Restores LINE-1 Methylation Levels in ARPE-19 Cells under Oxidative Stress and Inflammation.

The role of epigenetic alterations in the pathogenesis of retinal degenerative diseases, including age-related macular degeneration (AMD), has been pending so far. Our study investigated the effect of oxidative stress and inflammation on DNA methyltransferases (DNMTs) and Sirtuin 1 (SIRT1) functions, as well as on long interspersed nuclear element-1 (LINE-1) methylation, in human retinal pigment epithelial (ARPE-19) cells. Therefore, we evaluated whether treatment with resveratrol may modulate DNMT and SIRT1 functions and restore changes in LINE-1 methylation. Cells were treated with 25 mU/mL glucose oxidase (GOx) or 10 µg/mL lipopolysaccharide (LPS) to mimic oxidative or inflammatory conditions, respectively. Oxidative stress decreased DNMT1, DNMT3a, DNMT3b, and SIRT1 expression (p-values < 0.05), as well as total DNMTs (−28.5%; p < 0.0001) and SIRT1 (−29.0%; p < 0.0001) activities. Similarly, inflammatory condition decreased DNMT1 and SIRT1 expression (p-values < 0.05), as well as total DNMTs (−14.9%; p = 0.007) and SIRT1 (−20.1%; p < 0.002) activities. Interestingly, GOx- and LPS-treated cells exhibited lower LINE-1 methylation compared to controls (p-values < 0.001). We also demonstrated that treatment with 10 μM resveratrol for 24 h counteracted the detrimental effect on DNMT and SIRT1 functions, and LINE-1 methylation, in cells under oxidative and inflammatory conditions. However, further studies should explore the perspectives of resveratrol as a suitable strategy for the prevention and/or treatment of retinal degenerative diseases.

REST, regulated by RA through miR-29a and the proteasome pathway, plays a crucial role in RPC proliferation and differentiation

One of the primary obstacles in the application of retinal progenitor cells (RPCs) to the treatment of retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), is their limited ability to proliferate and differentiate into specific retinal neurons. In this study, we revealed that repressor element-1-silencing transcription factor (REST), whose expression could be transcriptionally and post-transcriptionally mediated by retinoic acid (RA, one isomeride of a vitamin A derivative used as a differentiation-inducing agent in many disease treatments), plays a pivotal role in the regulation of proliferation and differentiation of RPCs. Our results show that direct knockdown of endogenous REST reduced RPC proliferation but accelerated RPC differentiation toward retinal neurons, which phenocopied the observed effects of RA on RPCs. Further studies disclosed that the expression level of REST could be downregulated by RA not only through upregulating microRNA (miR)-29a, which directly interacted with the 3′-untranslated region (3′-UTR) of the REST mRNA, but also through promoting REST proteasomal degradation. These results show us a novel functional protein, REST, which regulates RPC proliferation and differentiation, can be mediated by RA. Understanding the mechanisms of REST and RA in RPC fate determination enlightens a promising future for the application of REST and RA in the treatment of retinal degeneration diseases.

AB006. The co-receptor CD36 as a target in regulation of subretinal inflammation

: Subretinal inflammation plays a critical role in retinal degenerative diseases. Although activated macrophages have been shown to play a key role in the progression of retinopathies and specifically in age-related macular degeneration, little is known about the mechanisms involved in the loss of photoreceptors leading to vision impairment. In our study on retinal damages induced by photo-oxidative stress, we have observed that CD36-deficient mice featured less subretinal macrophage accumulation with attenuated photoreceptor degeneration compared to wild-type (WT) mice. Treatment with CD36-selective azapeptide ligand (labelled MPE-001) as modulator of the inflammatory environment of the retina reduced subretinal macrophage/activated microglia accumulation with preservation of photoreceptor layers and function assessed by ERG in WT, in a CD36-dependent manner. The azapeptide modulated the transcriptome of subretinal macrophage/activated microglia by reducing pro-inflammatory markers. In isolated macrophages, the CD36-selective azapeptide induced dissociation of the CD36-TLR2/6 heterodimer complex (using FRET) altering the TLR2 signaling pathway, thus decreasing NF-KB activation and inflammasome activity. The azapeptide also incurred cytoprotection against photoreceptor apoptosis elicited by activated macrophages. These findings suggest that the azapeptide as ligand of co-receptor CD36 decreases the inflammatory response by modulating CD36-TLR2/6 complex signaling pathway in macrophages, and suggests its potential application in the treatment of retinal degenerative diseases.

Stem/Progenitor Cells and Biodegradable Scaffolds in the Treatment of Retinal Degenerative Diseases.

Visual impairment caused by retinal degeneration is primarily attributed to the irreversible degradation of retinal neurons or the adjacent retinal pigment epithelium (RPE). No efficient clinical therapies to restore or improve visual ability are currently available. Cell therapy has been touted as a promising strategy to overcome this challenge. This review aims to depict the effects and progresses of using stem/progenitor cells and biodegradable scaffolds in the treatment of retinal degenerative diseases, as well as discuss the challenges and opportunities of cell-based therapy for the future clinical application. Progenitor/stem cells may be obtained from both ocular and non-ocular tissues. The former mainly includes retinal progenitor cells (RPCs), whereas the latter comprises embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), which have been utilized in stem cell replacement therapy studies ranging from proof-of-concept animal models to clinical trials in humans. Mesenchymal stem cells (MSCs), which represent another type of stem cells, secrete anti-inflammatory cytokines and neurotrophic factors that protect and nourish retinae. Although the origins of seed cells are diverse, the cell survival rate after transplantation in vivo is limited. Therefore, cell delivery techniques that combine seed cells with polymer scaffolds are applied to improve the cell survival rate. This review summarized the different resources of stem cells and the significant progresses in the treatment of retinal degeneration combined with seed cells and scaffolds, which may pave the way for future clinical therapies.

Cell Transplantation for Retinal Degeneration: Transition from Rodent to Nonhuman Primate Models.

Transplantation of potentially therapeutic cells into the subretinal space is a promising prospective therapy for the treatment of retinal degenerative diseases including age-related macular degeneration (AMD). In rodent models with photoreceptor degeneration, subretinal transplantation of cell suspensions has repeatedly been demonstrated to rescue behaviorally measured vision, maintain electrophysiological responses from the retina and the brain, and slow the degeneration of rod and cone photoreceptors for extended periods. These studies have led to the initiation of a number of FDA-approved clinical trials for application of cell-based therapy for AMD and other retinal degenerative diseases. However, translation from rodent models directly into human clinical trials skips an important intermediary preclinical step that is needed to address critical issues for intraocular cell transplantation. These include determination of the most appropriate and least problematic surgical approach, the application of treatment in an eye with similar size and structure including the presence of a macula, and a thorough understanding of the immunological considerations regarding graft survival and the consequences of grafted cell rejection. This chapter will review these and related issues and will document current efforts to address these concerns.