scholarly journals Long-Term Transplant Effects of iPSC-RPE Monolayer in Immunodeficient RCS Rats

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2951
Author(s):  
Deepthi S. Rajendran Nair ◽  
Danhong Zhu ◽  
Ruchi Sharma ◽  
Juan Carlos Martinez Camarillo ◽  
Kapil Bharti ◽  
...  
Keyword(s):  
Cell Fate ◽  
Therapeutic Potential ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Subretinal Space ◽  
Long Term Effects ◽  
Rcs Rat ◽  
Age Related

Retinal pigment epithelium (RPE) replacement therapy is evolving as a feasible approach to treat age-related macular degeneration (AMD). In many preclinical studies, RPE cells are transplanted as a cell suspension into immunosuppressed animal eyes and transplant effects have been monitored only short-term. We investigated the long-term effects of human Induced pluripotent stem-cell-derived RPE (iPSC-RPE) transplants in an immunodeficient Royal College of Surgeons (RCS) rat model, in which RPE dysfunction led to photoreceptor degeneration. iPSC-RPE cultured as a polarized monolayer on a nanoengineered ultrathin parylene C scaffold was transplanted into the subretinal space of 28-day-old immunodeficient RCS rat pups and evaluated after 1, 4, and 11 months. Assessment at early time points showed good iPSC-RPE survival. The transplants remained as a monolayer, expressed RPE-specific markers, performed phagocytic function, and contributed to vision preservation. At 11-months post-implantation, RPE survival was observed in only 50% of the eyes that were concomitant with vision preservation. Loss of RPE monolayer characteristics at the 11-month time point was associated with peri-membrane fibrosis, immune reaction through the activation of macrophages (CD 68 expression), and the transition of cell fate (expression of mesenchymal markers). The overall study outcome supports the therapeutic potential of RPE grafts despite the loss of some transplant benefits during long-term observations.

scholarly journals Long-term Transplant Effects of iPSC-RPE Monolayer in Immunodeficient RCS Rats

2021 ◽  
Author(s):  
Deepthi S. Rajendran Nair ◽  
Danhong Zhu ◽  
Ruchi Sharma ◽  
Juan Carlos Martinez Camarillo ◽  
Kapil Bharti ◽  
...  
Keyword(s):  
Cell Fate ◽  
Therapeutic Potential ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Subretinal Space ◽  
Long Term Effects ◽  
Rcs Rat ◽  
Age Related

Retinal pigment epithelium (RPE) replacement therapy is evolving as a feasible approach to treat age-related macular degeneration (AMD). In majority of the preclinical studies, RPE cells are transplanted as cell suspension into immunosuppressed animal eyes and transplant effects were monitored only short-term. We investigated long-term effects of human iPSC derived RPE transplants in immunodeficient Royal College of Surgeons (RCS) rat model, in which RPE dysfunction lead to photoreceptor degeneration. iPSC-RPE cultured as polarized monolayer on nanoengineered ultrathin parylene C scaffold was transplanted into the subretinal space of 28-day old immunodeficient RCS rat pups and evaluated after 1, 4 and 11 months. Assessment at early time points showed good iPSC-RPE survival. The transplants remained as a monolayer, expressed RPE specific markers, performed phagocytic function and contributed to vision preservation. At 11-month post-implantation, RPE survival was observed only in 50% of the eyes that were concomitant with vision preservation. Loss of RPE monolayer characteristics at the 11month time point was associated with peri-membrane fibrosis, immune reaction through activation of macrophages (CD 68 expression) and transition of cell fate (expression of mesenchymal markers). The overall study outcome supports the therapeutic potential of RPE grafts despite the loss of some transplant benefits during long-term observations.

scholarly journals Pharmaceutical Induction of PGC-1α Promotes Retinal Pigment Epithelial Cell Metabolism and Protects against Oxidative Damage

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Sangeeta Satish ◽  
Hannah Philipose ◽  
Mariana Aparecida Brunini Rosales ◽  
Magali Saint-Geniez
Keyword(s):  
Cell Death ◽  
Antioxidant Enzymes ◽  
Oxidative Damage ◽  
Therapeutic Potential ◽  
Retinal Pigment Epithelial Cell ◽  
Cell Metabolism ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Age Related

Retinal pigment epithelium (RPE) dysfunction due to accumulation of reactive oxygen species and oxidative damage is a key event in the development of age-related macular degeneration (AMD). Here, we examine the therapeutic potential of ZLN005, a selective PGC-1α transcriptional regulator, in protecting RPE from cytotoxic oxidative damage. Gene expression analysis on ARPE-19 cells treated with ZLN005 shows robust upregulation of PGC-1α and its associated transcription factors, antioxidant enzymes, and mitochondrial genes. Energetic profiling shows that ZLN005 treatment enhances RPE mitochondrial function by increasing basal and maximal respiration rates, and spare respiratory capacity. In addition, ZLN005 robustly protects ARPE-19 cells from cell death caused by H2O2, ox-LDL, and NaIO3 without exhibiting any cytotoxicity under basal conditions. ZLN005 protection against H2O2-mediated cell death was lost in PGC-1α-silenced cells. Our data indicates that ZLN005 efficiently protects RPE cells from oxidative damage through selective induction of PGC-1α and its target antioxidant enzymes. ZLN005 may serve as a novel therapeutic agent for retinal diseases associated with RPE dystrophies.

scholarly journals Potential Treatment of Retinal Diseases with Iron Chelators

2018 ◽  
Vol 11 (4) ◽  
pp. 112 ◽  
Author(s):  
Wanting Shu ◽  
Joshua Dunaief
Keyword(s):  
Retinal Degeneration ◽  
Therapeutic Potential ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Body ◽  
Age Related Macular Degeneration ◽  
Hereditary Diseases ◽  
Iron Chelators ◽  
Excess Iron ◽  
Age Related

Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation. In addition to hereditary causes, dietary or parenteral iron supplementation has been recently reported to elevate iron levels in the retinal pigment epithelium (RPE) and promote retinal degeneration. Ocular siderosis from intraocular foreign bodies or subretinal hemorrhage can also lead to retinopathy. Evidence from mice and humans suggests that iron toxicity may contribute to age-related macular degeneration pathogenesis. Iron chelators can protect photoreceptors and RPE in various mouse models. The therapeutic potential for iron chelators is under investigation.

scholarly journals Beyond AREDS Formulations, What Is Next for Intermediate Age-Related Macular Degeneration (iAMD) Treatment? Potential Benefits of Antioxidant and Anti-inflammatory Apocarotenoids as Neuroprotectors

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Serge Camelo ◽  
Mathilde Latil ◽  
Stanislas Veillet ◽  
Pierre J. Dilda ◽  
René Lafont
Keyword(s):  
Macular Degeneration ◽  
Light Exposure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Crocus Sativus ◽  
Subretinal Space ◽  
Major Health Problem ◽  
Age Related

Age-related macular degeneration (AMD) is the commonest cause of severe visual loss and blindness in developed countries among individuals aged 60 and older. AMD slowly progresses from early AMD to intermediate AMD (iAMD) and ultimately late-stage AMD. Late AMD encompasses either neovascular AMD (nAMD) or geographic atrophy (GA). nAMD is defined by choroidal neovascularization (CNV) and hemorrhage in the subretinal space at the level of the macula. This induces a rapid visual impairment caused by the death of photoreceptor cells. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) antibodies is the standard treatment of nAMD but adds to the burden of patient care. GA is characterized by slowly expanding photoreceptor, and retinal pigment epithelium (RPE) degeneration patches progressively leading to blindness. There is currently no therapy to cure GA. Late AMD continues to be an unmet medical need representing a major health problem with millions of patients worldwide. Oxidative stress and inflammation are recognized as some of the main risk factors to developing late AMD. The antioxidant formulation AREDS (Age-Related Eye Disease Studies), contains β-carotene, which has been replaced by lutein and zeaxanthin in AREDS2, are given to patients with iAMD but have a limited effect on the incidence of nAMD and GA. Thus, to avoid or slowdown the development of late stages of AMD (nAMD or GA), new therapies targeting iAMD are needed such as crocetin obtained through hydrolysis of crocin, an important component of saffron (Crocus sativus L.), and norbixin derived from bixin extracted from Bixa orellana seeds. We have shown that these apocarotenoids preserved more effectively RPE cells against apoptosis following blue light exposure in the presence of A2E than lutein and zeaxanthin. In this review, we will discuss the potential use of apocarotenoids to slowdown the progression of iAMD, to reduce the incidence of both forms of late AMD.

scholarly journals Long-Term Outcomes of Rheohaemapheresis in the Treatment of Dry Form of Age-Related Macular Degeneration

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Jan Studnička ◽  
Eva Rencová ◽  
Milan Bláha ◽  
Pavel Rozsíval ◽  
Miriam Lánská ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Treated Patient ◽  
Pigment Epithelium ◽  
Age Related Macular Degeneration ◽  
Rheological Parameters ◽  
Control Group ◽  
Long Term Effects ◽  
Age Related

Purpose. Determining long-term effects of rheohaemapheresis on the dry form of age-related macular degeneration.Methods. This study evaluates 19 patients, average age of 67.6 years, treated with rheohaemapheresis and 18 patients, average age of 72.8 years, comprising the control group. Minimum follow up period was 3.5 years. Each treated patient received a series of 8 sessions of rheohaemapheresis of 1.5 plasma volumes within 10 weeks. We measured the drusenoid pigment epithelium detachment (DPED), best-corrected visual acuity (BCVA), electroretinography (ERG), and rheological parameters.Results. In the treatment group, the baseline BCVA was 0.74 (0.36–1.0) 95% CI and BCVA after 3.5 years was 0.79 (0.41–1.0) 95% CI (P=0.726). In the control group, the baseline BCVA was 0.71 (0.15–1.0) 95% CI and BCVA after 3.5 years decreased to 0.7 (0.32–0.87) 95% CI (P=0.031). Baseline DPED was 6.78 ± 3.79 mm2; after 3.5 years, it decreased to 4.13 ± 3.84 mm2(P<0.001). In the control group, the baseline DPED was 4.09 ± 3.48 mm2; after 3.5 years, it increased to 6.69 ± 4.2 mm2(P=0.001). We noted increasing levels of positive wave peaking at 50 milliseconds (P50) after treatment (P=0.022) and a stable amplitude of photopic responses of treated patients.Conclusion. Over the long term, rheohaemapheresis reduced the DPED, improved the function of photoreceptors, and prevented the decline of BCVA.

Clinical and Functional Characteristics of Secondary Geographic Atrophy Against the Background of Exudative Age-Related Macular Degeneration

2021 ◽  
Vol 76 (4) ◽  
pp. 384-393
Author(s):  
Vladimir V. Neroev ◽  
Marina V. Zueva ◽  
Natalia V. Neroeva ◽  
Ludmila A. Katargina ◽  
Oksana A. Losanova ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Antiangiogenic Therapy ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Flicker Erg ◽  
Wet Amd

Background.Studies demonstrate the need for long-term follow-up of patients with wet age-related macular degeneration (AMD) treated with inhibitors of angiogenesis to monitor long-term vision outcomes and assess the safety of antiangiogenic therapy in relation to the risk of secondary geographic atrophy. Aims to determine the characteristic clinical and functional signs of secondary GA that developed against the background of wet AMD. Methods.In 22 patients (25 eyes) with wet AMD and 18 healthy subjects comparable in age and sex standard ophthalmological and instrumental studies were performed and photopic electroretinograms (ERGs) were recorded according to ISCEV standards, flicker-ERGs, multifocal ERGs and electrooculogram. Results.The appearance of the area of secondary atrophy against the background of wet AMD in eyes treated with inhibitors of angiogenesis is clinically indistinguishable from areas of geographic atrophy that developed as an outcome of dry AMD. The ERG-signs of secondary atrophy are described, which are similar to the biomarkers of primary atrophy and specifically differ from them. Secondary atrophy is characterized by the dependence of the increase in the b/a ratio on the atrophic area, reducing of the 8.3 Hz-flicker-ERG amplitude in the absence of 24 Hz-flicker ERG changes. In eyes with secondary atrophy, a significant decrease in the density of the multifocal ERG P1-peak was shown not only in the first hexagon but also in the parafoveal zone. The electrooculography results showed a sharper dark troughs decrease in with an increase in Ardens ratio in patients with secondary atrophya on the background of wet AMD, in contrast to the previously described changes in primary geographic atrophy. Conclusion.Comparison of the change in the b/a ratio with secondary atrophy area in patients with wet AMD may have clinical implications for assessing retinal dysfunction and predicting visual function. Secondary atrophy is associated with a pronounced inhibition of photoreceptor activity with better preservation of cone bipolar cells. The ERG and electrooculography data taking together indicate a more significant dysfunction of the retinal pigment epithelium in GA against the background of wet AMD and the associated deterioration of photoreceptor function than the changes characterizing primary geographic atrophy.

scholarly journals Antiangiogenic and Neurogenic Activities ofSleeping Beauty-Mediated PEDF-Transfected RPE CellsIn VitroandIn Vivo

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Sandra Johnen ◽  
Yassin Djalali-Talab ◽  
Olga Kazanskaya ◽  
Theresa Möller ◽  
Nina Harmening ◽  
...  
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Sleeping Beauty ◽  
Biologically Active ◽  
Age Related Macular Degeneration ◽  
Subretinal Space ◽  
Transfected Cells ◽  
Rpe Cells ◽  
Pigment Epithelial ◽  
Age Related

Pigment epithelium-derived factor (PEDF) is a potent multifunctional protein that inhibits angiogenesis and has neurogenic and neuroprotective properties. Since the wet form of age-related macular degeneration is characterized by choroidal neovascularization (CNV), PEDF would be an ideal candidate to inhibit CNV and support retinal pigment epithelial (RPE) cells. However, its short half-life has precluded its clinical use. To deliver PEDF to the subretinal space, we transfected RPE cells with thePEDFgene using theSleeping Beautytransposon system. Transfected cells expressed and secreted biologically active recombinant PEDF (rPEDF). In cultures of human umbilical vein endothelial cells, rPEDF reduced VEGF-induced cumulative sprouting by ≥47%, decreased migration by 77%, and increased rate of apoptosis at least 3.4 times. rPEDF induced neurite outgrowth in neuroblastoma cells and protected ganglion and photoreceptor cells in organotypic retinal cultures. In a rat model of CNV, subretinal transplantation of PEDF-transfected cells led to a reduction of the CNV area by 48% 14 days after transplantation and decreased clinical significant lesions by 55% and 40% after 7 and 14 days, respectively. We showed that transplantation of pigment epithelial cells overexpressingPEDFcan restore a permissive subretinal environment for RPE and photoreceptor maintenance, while inhibiting choroidal blood vessel growth.

scholarly journals Role of FGF and Hyaluronan in Choroidal Neovascularization in Sorsby Fundus Dystrophy

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 608
Author(s):  
Alyson Wolk ◽  
Dilara Hatipoglu ◽  
Alecia Cutler ◽  
Mariya Ali ◽  
Lestella Bell ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Rpe Cells ◽  
Age Related ◽  
Sorsby's Fundus Dystrophy

Sorsby’s fundus dystrophy (SFD) is an inherited blinding disorder caused by mutations in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene. The SFD pathology of macular degeneration with subretinal deposits and choroidal neovascularization (CNV) closely resembles that of the more common age-related macular degeneration (AMD). The objective of this study was to gain further insight into the molecular mechanism(s) by which mutant TIMP3 induces CNV. In this study we demonstrate that hyaluronan (HA), a large glycosaminoglycan, is elevated in the plasma and retinal pigment epithelium (RPE)/choroid of patients with AMD. Mice carrying the S179C-TIMP3 mutation also showed increased plasma levels of HA as well as accumulation of HA around the RPE in the retina. Human RPE cells expressing the S179C-TIMP3 mutation accumulated HA apically, intracellularly and basally when cultured long-term compared with cells expressing wildtype TIMP3. We recently reported that RPE cells carrying the S179C-TIMP3 mutation have the propensity to induce angiogenesis via basic fibroblast growth factor (FGF-2). We now demonstrate that FGF-2 induces accumulation of HA in RPE cells. These results suggest that the TIMP3-MMP-FGF-2-HA axis may have an important role in the pathogenesis of CNV in SFD and possibly AMD.

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