Scaffolds for retinal pigment epithelial cell transplantation in age-related macular degeneration.
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ABSTRACT:
SUBMITTER: White CE
PROVIDER: S-EPMC5524239 | biostudies-other | 2017 Jan-Dec
REPOSITORIES: biostudies-other
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Project description:This pilot study evaluated the combination of photodynamic therapy (PDT) and anti-vascular endothelial growth factor (anti-VEGF) as a treatment in patients with a pigment epithelial detachment (PED) due to exudative age-related degeneration (AMD).We analyzed seven consecutive patients between September 1, 2015 and September 1, 2017 with a PED secondary to exudative AMD who were treated with full fluence standard PDT and a series of monthly intravitreal anti-VEGF injections. Follow-up ranged between 3 and 24 months. Variables collected for the purpose of this study included baseline best-corrected visual acuity converted to logMAR (logarithm of minimum angle of resolution), central macular thickness, and maximum PED height. This information was then reviewed at subsequent follow-ups.The PED completely resolved in 4/7 eyes while three patients had a significant improvement in PED size with a corresponding improvement in visual acuity. Initial PED heights ranged from 147 to 423??m and was reduced by an average of 255.7??m (83.2% average reduction, range -143 to - 405??m). Initial CMT ranged from 223 to 719??m and was reduced by an average of 225.7??m (54.4% average reduction, range -88 to - 529??m). Mean logMAR VA improved from 0.669 (Snellen equivalent 20/93, [20/40 to 20/200]) to 0.269 (Snellen equivalent 20/37, [20/25 to 20/80]) at last follow-up. No complications were observed in our patients.PED in the setting of exudative AMD showed an excellent response to a combined multimodal approach that includes PDT with intravitreal anti-VEGF injection followed by a monthly anti-VEGF schedule. Most importantly, visual acuity showed a significant improvement from baseline. If confirmed by future studies, this would offer another treatment avenue for this difficult-to-treat consequence of exudative AMD.
| S-EPMC5786863 | biostudies-other
Project description:Retinal cell therapy can have the objectives of rescue (i.e., modulation of metabolic abnormalities primarily for sight preservation) as well as replacement (i.e., replace cells lost due to injury or disease for sight restoration as well as preservation). The first clinical trials of retinal pigment epithelium (RPE) transplantation for vision-threatening complications of age-related macular degeneration (AMD) have begun with some preliminary signs of success (e.g., improvement in vision in some patients, anatomic evidence of transplant-host integration with some evidence of host photoreceptor recovery, long-term survival of autologous induced pluripotent stem cell-derived RPE transplants without immune suppression) as well as limitations (e.g., limited RPE suspension survival in the AMD eye, limited tolerance for long-term systemic immune suppression in elderly patients, suggestion of uncontrolled cell proliferation in the vitreous cavity). RPE survival on aged and AMD Bruch's membrane can be improved with chemical treatment, which may enhance the efficacy of RPE suspension transplants in AMD patients. Retinal detachment, currently used to deliver transplanted RPE cells to the subretinal space, induces disjunction of the first synapse in the visual pathway: the photoreceptor-bipolar synapse. This synaptic change occurs even in areas of attached retina near the locus of detachment. Synaptic disjunction and photoreceptor apoptosis associated with retinal detachment can be reduced with Rho kinase inhibitors. Addition of Rho kinase inhibitors may improve retinal function and photoreceptor survival after subretinal delivery of cells either in suspension or on scaffolds.
| S-EPMC6477002 | biostudies-literature
Project description:Background: Different sources of retinal pigment epithelial cells (RPE) were transplanted to treat Age-related Macular Degeneration. But the mechanisms of therapeutic effect are unclear till now, and GMP level fetal RPE (fRPE) need further evaluation for treatment. Methods: Modified GMP fRPE primary culture system was founded. These RPE were tested on Mer-/- mice and sodium iodate induced retinopathy primate model for safety and feasibility. Five dry-AMD patients and one Stargardt’s Disease patient were enrolled, and received sub retinal transplantation of hfRPE with three dosage cohorts(1×105，2×105，5×105). ETDRS, optic coherent tomographic imaging (OCT), color fundus (CF), fluorescent angiography (FFA), autofluorescence, microperimetry examination were conducted before surgery, and during follow-up period. The studies are registered with ClinicalTrials.gov, numbers NCT02868424. Findings: GMP level fRPE from modified primary culture system has good proliferative capacity and full functions of RPE in vitro. Human fetal RPE can survive long period in sub-retinal space in mice and monkey models of RPE degeneration, and showed therapeutic effect on Mer-/- mice. During our nine-months follow-up of six clinical cases, no endophthalmitis, no vitreous hemorrhage, no proliferative vitreoretinopathy was observed, and epiretinal memrbrane was the only complication. Among the patients, four of them achieved increase in ETDRS visual acuity (VA), of which the greatest improvement was 18 letters, and one kept steady while the other had 9 letters decreased VA. Color fundus photos and OCT demonstrated the existence of the fRPE cells, and improved retinal sensitivity as well as the changes observed in auto fluorescence also can tell the situation of grafted cells to some extent. Interpretation: GMP level fRPE from modified culture system exhibited satisfactory results on in vitro and preclinical experiments. Preliminary clinical trial proved safety of the fRPE subretinal transplantation, and substantiated it a promising therapy for dry AMD including the converted from exudative AMD.
2018-05-22 | GSE99240 | GEO
Project description:The purpose of this study was to quantitatively evaluate retinal pigment epithelium (RPE) changes in serous pigment epithelial detachment (PED) among patients with age-related macular degeneration by means of prototype multi-contrast optical coherence tomography (OCT), which is capable of simultaneous collection of OCT angiography, polarization-sensitive OCT, and standard OCT images. We evaluated 26 eyes of 21 patients with serous PED. RPE-melanin OCT images were calculated from the multi-contrast OCT dataset and compared with near-infrared autofluorescence images. An active RPE lesion was defined as an area of thickened RPE-melanin (≥ 70 μm; RPE70) on RPE-melanin OCT. Each PED area was divided into peak and slope regions. RPE70 area ratios were compared with the maximum PED height, PED area, PED volume, and slope area ratio (area of slope region/area of whole PED). RPE-melanin OCT images were consistent with near-infrared autofluorescence images. The RPE70 area ratio in the slope region was significantly negatively correlated with the slope area ratio. Development of active RPE lesions in the slope region was correlated with the PED configuration. Multi-contrast OCT is useful for objective evaluation of changes in the RPE in patients with age-related macular degeneration.
| S-EPMC7854605 | biostudies-literature
Project description:To identify disease-specific transcriptional programs in retinal pigment epithelium (RPE) cells, fibroblasts from 43 patients with geographic atrophy (GA) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into RPE and compared to those from 36 healthy individuals. 127,659 RPE cells were profiled via single cell RNA-sequencing (scRNA-seq) and cell classification identified 7 cellular states related to RPE maturation.
2022-06-20 | E-MTAB-11642 | biostudies-arrayexpress
Project description:Primary cultures of retinal pigment epithelium (RPE) from human adult donors (haRPE) and induced pluripotent stem cell derived-RPE (iPSC-RPE) are valuable model systems for gaining mechanistic insight and for testing potential therapies for age-related macular degeneration (AMD). This study evaluated the treatment response of haRPE and iPSC-RPE to oxidative stress and potential therapeutics addressing mitochondrial defects. haRPE and iSPC-RPE were derived from donors with or without AMD. Mitochondrial function was measured after treatment with menadione, AICAR, or trehalose and the response to treatment was compared between cell models and by disease status. In a subset of samples, haRPE and iPSC-RPE were generated from the same human donor to make a side-by-side comparison of the two cell models' response to treatment. Disease-specific responses to all three treatments was observed in the haRPE. In contrast, iPSC-RPE had a similar response to all treatments irrespective of disease status. Analysis of haRPE and iPSC-RPE generated from the same human donor showed a similar response for donors without AMD, but there were significant differences in treatment response between cell models generated from AMD donors. These results support the use of iPSC-RPE and haRPE when investigating AMD mechanisms and new therapeutics but indicates that attention to experimental conditions is required.
| S-EPMC9025527 | biostudies-literature
Project description:Mitochondrial damage and epigenetic modifications have been implicated in the pathogenesis of Age-related Macular Degeneration (AMD). This study was designed to investigate the effects of AMD/normal mitochondria on epigenetic regulation in human transmitochondrial retinal pigment epithelial (RPE) cells in vitro. Human RPE cybrid cell lines were created by fusing mitochondria-deficient (Rho0) ARPE-19 cells with platelets obtained from either AMD patients (AMD cybrids) or normal subjects (normal cybrids). Therefore, all cybrids had identical nuclei (derived from ARPE-19 cells) but mitochondria derived from either AMD patients or age-matched normal subjects. AMD cybrids demonstrated increased RNA/protein levels for five methylation-related and four acetylation-related genes, along with lower levels of two methylation and three acetylation genes compared to normal cybrids. Demethylation using 5-Aza-2'-deoxycytidine (DAC) led to decreased expression of VEGF-A gene in AMD cells. Trichostatin A (TSA), an HDAC inhibitor, also influenced protein levels of VEGF-A, HIF1α, NFκB, and CFH in AMD cells. Our findings suggest that retrograde signaling leads to mitochondria-nucleus interactions that influence the epigenetic status of the RPE cells and this may help in the identification of future potential therapeutic targets for AMD.
| S-EPMC7192350 | biostudies-literature
Project description:PURPOSE:Transplantation of human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells offers the potential for benefit in macular degeneration. Previous trials have reported improved visual acuity (VA), but lacked detailed analysis of retinal structure and function in the treated area. DESIGN:Phase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832). PARTICIPANTS:Twelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults. METHODS:Subretinal transplantation of up to 200?000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks. MAIN OUTCOME MEASURES:The primary end points were the safety and tolerability of hESC-derived RPE cell administration. We also investigated evidence of the survival of transplanted cells and measured retinal structure and function using microperimetry and spectral-domain OCT. RESULTS:Focal areas of subretinal hyperpigmentation developed in all participants in a dose-dependent manner in the recipient retina and persisted after withdrawal of systemic immunosuppression. We found no evidence of uncontrolled proliferation or inflammatory responses. Borderline improvements in best-corrected VA in 4 participants either were unsustained or were matched by a similar improvement in the untreated contralateral eye. Microperimetry demonstrated no evidence of benefit at 12 months in the 12 participants. In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm. Participant-reported quality of life using the 25-item National Eye Institute Visual Function Questionnaire indicated no significant change. CONCLUSIONS:Subretinal hyperpigmentation is consistent with the survival of viable transplanted hESC-derived RPE cells, but may reflect released pigment in their absence. The findings demonstrate the value of detailed analysis of spatial correlation of retinal structure and function in determining with appropriate sensitivity the impact of cell transplantation and suggest that intervention in early stage of disease should be approached with caution. Given the slow rate of progressive degeneration at this advanced stage of disease, any protection against further deterioration may be evident only after a more extended period of observation.
| S-EPMC6195794 | biostudies-literature
Project description:Although age-related macular degeneration (AMD) is a multifactorial disorder with angiogenic, immune, and inflammatory components, the most common clinical treatment strategies are antiangiogenic therapies. However, these strategies are only applicable to neovascular AMD, which accounts for less than 20% of all AMD cases, and there are no FDA-approved drugs for the treatment of dry AMD, which accounts for ~ 80% of AMD cases. Here, we report that the elimination of senescent cells is a potential novel therapeutic approach for the treatment of all types of AMD. We identified senescent retinal pigment epithelium (RPE) cells in animal models of AMD and determined their contributions to retinal degeneration. We further confirmed that the clearance of senescent RPE cells with the MDM2-p53 inhibitor Nutlin-3a ameliorated retinal degeneration. These findings provide new insights into the use of senescent cells as a therapeutic target for the treatment of AMD.
| S-EPMC8602547 | biostudies-literature
Project description:PURPOSE: To monitor retinal pigment epithelial (RPE) atrophy progression during antiangiogenic therapy of neovascular age-related macular degeneration (AMD) over 2 years using polarization-sensitive optical coherence tomography (OCT). DESIGN: Prospective interventional case series. METHODS: setting: Clinical practice. STUDY POPULATION: Thirty patients (31 eyes) with treatment-naïve neovascular AMD. OBSERVATION PROCEDURES: Standard intravitreal therapy (0.5 mg ranibizumab) was administered monthly during the first year and pro re nata (PRN; as-needed) during the second year. Spectral-domain (SD) OCT and polarization-sensitive OCT (selectively imaging the RPE) examinations were performed at baseline and at 1, 3, 6, 12, and 24 months using a standardized protocol. RPE-related changes were evaluated using a semi-automated polarization-sensitive OCT segmentation algorithm and correlated with SD OCT and fundus autofluorescence (FAF) findings. MAIN OUTCOME MEASURES: RPE response, geographic atrophy (GA) progression. RESULTS: Atrophic RPE changes included RPE thinning, RPE porosity, focal RPE atrophy, and development of GA. Early RPE loss (ie, RPE porosity, focal atrophy) increased progressively during initial monthly treatment and remained stable during subsequent PRN-based therapy. GA developed in 61% of eyes at month 24. Mean GA area increased from 0.77 mm(2) at 12 months to 1.10 mm(2) (standard deviation = 1.09 mm(2)) at 24 months. Reactive accumulation of RPE-related material at the lesion borders increased until month 3 and subsequently decreased. CONCLUSIONS: Progressive RPE atrophy and GA developed in the majority of eyes. RPE migration signifies certain RPE plasticity. Polarization-sensitive OCT specifically images RPE-related changes in neovascular AMD, contrary to conventional imaging methods. Polarization-sensitive OCT allows for precisely monitoring the sequence of RPE-related morphologic changes.
| S-EPMC4430174 | biostudies-literature