Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration

Mehat, Manjit; Sundaram, V.; Ripamonti, Caterina; Robson, Anthony G.; Smith, Alexander J.; Borooah, Shyamanga; Robinson, Martha; Rosenthal, Adam N.; Innes, William A.; Weleber, Richard G.; Lee, Richard W.; Crossland, Michael D.; Rubin, Gary S.; Dhillon, Baljean; Steel, David; Anglade, Eddy; Lanza, Robert; Ali, Robin R.; Michaelides, Michel; Bainbridge, James

doi:10.1016/j.ophtha.2018.04.037

Cited by 200 publications

(194 citation statements)

References 21 publications

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“…Cell transplantation using embryonic stem cells (ESCs) or induced pluripotent stem cell (iPSC)-derived RPE cells is a promising therapy for AMD. [42][43][44] ESC/iPSC-derived RPE cells are largely applied to AMD patients in the most advanced stage. Therefore, seeking novel therapies or drugs that can rescue RPE cells from death will strongly benefit patients in the progressive stages.…”

Section: Discussionmentioning

confidence: 99%

D609 protects retinal pigmented epithelium as a potential therapy for age-related macular degeneration

Wang

et al. 2020

Sig Transduct Target Ther

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Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium (RPE) cell death, which is considered to be the primary cause of dry age-related macular degeneration (AMD), leading to blindness in the elderly. However, an effective therapy for this disease is lacking. Here, we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate (SI)-induced oxidative cell death and prolonged their healthy survival. D609 effectively attenuated excessive reactive oxygen species (ROS) and prevented severe mitochondrial loss due to oxidative stress in the RPE cells. Surprisingly, the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein. The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model. These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609, which may ultimately have clinical applications for the treatment of AMD.Signal Transduction and Targeted Therapy (2020) 5:20; https://doi.

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Section: Discussionmentioning

confidence: 99%

D609 protects retinal pigmented epithelium as a potential therapy for age-related macular degeneration

Wang

et al. 2020

Sig Transduct Target Ther

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“…Various cellular grafts (e.g. photoreceptor precursors, RPE cells, bone marrow cells, umbilical tissue cells, and others) have been studied in small and large animal transplantation models 3,25–29 , en route to human application 30–34 . A typical goal in preclinical retinal cell therapy research is to assess the long-term structural outcomes (e.g.…”

Section: Discussionmentioning

confidence: 99%

QuantifiableIn VivoImaging Biomarkers of Retinal Regeneration by Photoreceptor Cell Transplantation

Liu

Sodhi

Xue

et al. 2019

Preprint

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32Purpose: Short-term improvements in retinal anatomy are known to occur in preclinical models 33 of photoreceptor transplantation. However, correlative changes over the long term are poorly 34 understood. We aimed to develop a quantifiable imaging biomarker grading scheme, using non-35 invasive multimodal confocal scanning laser ophthalmoscopy (cSLO) imaging, to enable serial 36 evaluation of photoreceptor transplantation over the long term. 37Methods: Yellow-green fluorescent microspheres were transplanted into the vitreous cavity 38 and/or subretinal space of C57/BL6J mice. Photoreceptor cell suspensions or sheets from 39 rhodopsin-green fluorescent protein mice were transplanted subretinally, into either NOD.CB17-40 Prkdc scid /J or C3H/HeJ-Pde6b rd1 mice. Multimodal cSLO imaging was performed serially for up 41 to three months after transplantation. Imaging biomarkers were scored, and a grade was defined 42 for each eye by integrating the scores. Image grades were correlated with immunohistochemistry 43 (IHC) data. 44 Results: Multimodal imaging enabled the extraction of quantitative imaging biomarkers 45 including graft size, GFP intensity, graft length, on-target graft placement, intra-graft lamination, 46 hemorrhage, retinal atrophy, and peri-retinal proliferation. Migration of transplanted material 47 increasing the efficiency of preclinical retinal cell transplantation studies in rodents and other 53 animal models. 54 Key words: degenerative retinal diseases, age-related macular degeneration, stem cell therapy, 55 xenotransplantation, photoreceptor cell, retinal organoid, confocal scanning laser 56 ophthalmoscopy 57 Photoreceptor transplantation is being developed as a therapeutic modality to restore vision in 59 people affected by retinal degenerative diseases, including retinitis pigmentosa (RP) and age-60 related macular degeneration (AMD) 1-6 . Short term improvements in outer retinal anatomy after 61 photoreceptor cell transplantation have been observed, mainly by histological staining in 62 preclinical models of retinal degeneration 4,7 . However, histology is a relatively inefficient 63 method to track graft and recipient anatomy longitudinally over the long term. Histological 64 assays are labor-intensive, require large initial cohorts of recipients, and face the challenge of 65 recipient attrition over time. Non-invasive imaging could facilitate the longitudinal evaluation of 66 retinal anatomy in relatively smaller cohorts of recipient animals over time, without the need to 67 sacrifice animals at every assessment time point. 68 Recent advances in imaging techniques have enabled detailed imaging studies in mouse models 69 of retinal disease and regeneration 8-10 . Confocal scanning laser ophthalmoscopy (cSLO) can be 70 used to capture images in multiple imaging modes, including short-wavelength fluorescence 71 (SWF) excitation (488 nm) to detect photoreceptor cells labeled with green fluorescent protein 72 (GFP) in mouse recipients 1 . Multicolor reflectance (MR) imaging combines blue (488 nm)...

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“…1c and f). The distribution of observational clinical studies across the globe was as follows: 41.6% (42) of the trials took place in the USA, 16.8% (17) in France, 7.9% (8) in Japan, 5.9% (6) in the UK, 6.9% (7) in Israel, 5.0% (5) in Germany and 5.0% (5) in China (see Fig. 1d and g).…”

Section: Global Distribution Of Clinical Trials Involving Pluripotentmentioning

confidence: 99%

“…The essence of iPSCs is that a mature, nally differentiated cell is reprogrammed via insertion of a set of genes, generating a pluripotent cell line for a speci c patient (8). Since the rst report on iPSCs by Yamanaka et al in 2006 (9), we have experienced publication of a plethora of studies involving preclinical in vitro (10,11) and in vivo (12)(13)(14)(15)(16) as well as rst clinical studies in humans (5,17,18) investigating the feasibility and safety of ESCs and iPSCs for therapeutic applications. Ongoing efforts to realize stem cell based therapies for ophthalmic diseases and neurological disorders have so far shown identi ed.…”

Section: Introductionmentioning

confidence: 99%

Global trends in clinical trials involving pluripotent stem cells: A systematic multi-database analysis

Deinsberger

Reisinger

Weber

2020

Preprint

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Background: Pluripotent stem cells (PSCs) hold great potential for novel therapeutic approaches to regenerate or replace functionally impaired tissues. Since the introduction of the induced pluripotent stem cell technology in 2006, the number of scientific publications on this topic has constantly been increasing. However, so far no therapy based on PSCs has found its way into routine clinical use. Methods: In this study, we examined research trends related to clinical trials involving PSCs based on data obtained from ClinicalTrial.gov, the ICTRP database from the World Health Organization, as well as from a search of all individual databases that are included in the ICTRP using a multistep search algorithm. Results: 131 studies could be classified as clinical trials involving PSCs and were included into further analyses. The magnitude of these studies (77.1%) was observational, which implies that no cells were transplanted into patients, and only a minority of studies (22.9%) had an interventional character. The number of clinical trials involving induced pluripotent stem cells (iPSCs, 74.8%) was substantially higher than the one involving embryonic stem cells (ESCs, 25.2%). However, the picture changes when focusing on interventional studies, where in the majority (73.3%) of cases ESCs were used. Interestingly, the study duration was significantly shorter for interventional versus observational trials (p=0.002). When focusing on the geographical study regions, it became obvious that the greatest part of all observational trials was performed in the USA (41.6%) and in France (16.8%), while the magnitude of interventional studies was performed in Asian countries (China 36.7%, Japan 13.3%, South Korea 10.0%) and in the field of ophthalmology. Conclusions: These results indicate that only a limited number of trials were focusing on the actual transplantation of PSCs into patients in a rather narrow field of diagnoses. The majority of interventional trials involving PSCs took place in Asian countries and in the field of ophthalmology. The future will tell us, if the iPSC technology will ultimately overcome the current challenges and will finally make its way into routine clinical use.

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Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration

Cited by 200 publications

References 21 publications

D609 protects retinal pigmented epithelium as a potential therapy for age-related macular degeneration

D609 protects retinal pigmented epithelium as a potential therapy for age-related macular degeneration

QuantifiableIn VivoImaging Biomarkers of Retinal Regeneration by Photoreceptor Cell Transplantation

Global trends in clinical trials involving pluripotent stem cells: A systematic multi-database analysis

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