Vision Improvement in Retinal Degeneration Patients by Implantation of Retina Together with Retinal Pigment Epithelium

Radtke, Norman D.; Aramant, Robert B.; Petry, Heywood M.; Green, Parke T.; Pidwell, Diane J.; Seiler, Magdalene J.

doi:10.1016/j.ajo.2008.04.009

Cited by 224 publications

(195 citation statements)

References 45 publications

(54 reference statements)

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“…These studies were then applied to patients and transplantation of human fetal retinal sheets was found to improve the vision of patients transiently for a period of 3 to 13 months [9]. Clinical trials transplanting sheets of fetal donor retina and RPE cells into patients are ongoing in the United States (http://clinicaltrials.gov/ct2/show/NCT00345917; http://clinicaltrials.gov/ct2/show/NCT00346060 [10]) and Germany (clinicaltrials.gov NCT00401713, [11]). These trials demonstrate that human retinal transplantation is feasible, and they hold the promise of visual recovery for otherwise hopeless retinal disease [12].…”

Section: Retinal Replacement Therapymentioning

confidence: 99%

Stem Cells for Retinal Replacement Therapy

Stern

Temple

2011

Neurotherapeutics

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Retinal degenerative disease has limited therapeutic options and the possibility of stem cell-mediated regenerative treatments is being actively explored for these blinding retinal conditions. The relative accessibility of this central nervous system tissue and the ability to visually monitor changes after transplantation make the retina and adjacent retinal pigment epithelium prime targets for pioneering stem cell therapeutics. Prior work conducted for several decades indicated the promise of cell transplantation for retinal disease, and new strategies that combine these established surgical approaches with stem cell-derived donor cells is ongoing. A variety of tissue-specific and pluripotent-derived donor cells are being advanced to replace lost or damaged retinal cells and/or to slow the disease processes by providing neuroprotective factors, with the ultimate aim of long-term improvement in visual function. Clinical trials are in the early stages, and data on safety and efficacy are widely anticipated. Positive outcomes from these stem cell-based clinical studies would radically change the way that blinding disorders are approached in the clinic.

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Section: Retinal Replacement Therapymentioning

confidence: 99%

Stem Cells for Retinal Replacement Therapy

Stern

Temple

2011

Neurotherapeutics

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“…Photoreceptors (PRs) and the retinal pigment epithelium (RPE) are commonly considered the most important targets of stem cell therapies [1][2][3]. PRs and RPE interact functionally and structurally [2][3][4][5][6], appear to polarize each other [7], and are reported to show improved engraftment when transplanted together [8,9]. After engraftment, stem cell-derived PRs must survive and form functional synaptic connections.…”

mentioning

confidence: 99%

“…This facilitates subsequent subretinal grafting and likely the survival of PRs. Retinal repair with human fetal grafts and vision improvements have been achieved in animals [14,28] and in patients with advanced retinal degeneration [9,[29][30][31]. Self-organization of 3D retinal tissue is especially efficient if the transplant includes the RPE [8,9,30,32].…”

mentioning

confidence: 99%

Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures

Singh

Mallela

Cornuet

et al. 2015

Stem Cells and Development

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Stem cell-based therapy of retinal degenerative conditions is a promising modality to treat blindness, but requires new strategies to improve the number of functionally integrating cells. Grafting semidifferentiated retinal tissue rather than progenitors allows preservation of tissue structure and connectivity in retinal grafts, mandatory for vision restoration. Using human embryonic stem cells (hESCs), we derived retinal tissue growing in adherent conditions consisting of conjoined neural retina and retinal pigment epithelial (RPE) cells and evaluated cell fate determination and maturation in this tissue. We found that deriving such tissue in adherent conditions robustly induces all eye field genes (RX, PAX6, LHX2, SIX3, SIX6) and produces four layers of pure populations of retinal cells: RPE (expressing NHERF1, EZRIN, RPE65, DCT, TYR, TYRP, MITF, PMEL), early photoreceptors (PRs) (coexpressing CRX and RCVRN), inner nuclear layer neurons (expressing CALB2), and retinal ganglion cells [RGCs, expressing BRN3B and Neurofilament (NF) 200]. Furthermore, we found that retinal progenitors divide at the apical side of the hESC-derived retinal tissue (next to the RPE layer) and then migrate toward the basal side, similar to that found during embryonic retinogenesis. We detected synaptogenesis in hESC-derived retinal tissue, and found neurons containing many synaptophysin-positive boutons within the RGC and PR layers. We also observed long NF200-positive axons projected by RGCs toward the apical side. Whole-cell recordings demonstrated that putative amacrine and/or ganglion cells exhibited electrophysiological responses reminiscent of those in normal retinal neurons. These responses included voltagegated Na + and K + currents, depolarization-induced spiking, and responses to neurotransmitter receptor agonists. Differentiation in adherent conditions allows generation of long and flexible pieces of 3D retinal tissue suitable for isolating transplantable slices of tissue for retinal replacement therapies.

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“…24 Crucial [25][26][27] In addition to transplanting fetal RPE, transplantation of a fetal neuroretina/RPE complex in a 64-year-old woman with retinitis pigmentosa resulted in improvement in visual acuity at 5-year follow-up. 28 However, this appears to be an isolated case because no such change was observed in any other patient studied. In addition, the patients who could tolerate the triple immunosupression for 6 months showed no apparent immune rejection.…”

Section: Fetal Rpe Cellsmentioning

confidence: 69%

Replacement of the RPE monolayer

Sheridan

Mason

Pattwell

et al. 2009

Eye

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There are numerous scenarios in which replacing the diseased RPE monolayer is an attractive but as yet unrealised goal. The proof of concept that vision can be improved by placing a healthy neuroretina onto a different, healthy, underlying RPE layer is demonstrated in patch graft transplantations. The surgical procedure to relocate the neuroretina is both complex and is hampered by postoperative complications and as such newer replacement procedures are also being investigated including stem cell replacement therapies. Past studies have largely focused on using cell suspensions and have had disappointing outcomes largely due to the lack of control over cellular differentiation, incomplete attachment onto Bruch's membrane and subsequent integration into the existing RPE monolayer. The choice of which cells to transplant is still under investigation and is complicated by factors such as the ease of collection of an adequate sample, rejection following implantation, the age of the cells and ethical issues. In all these situations, however, understanding the mechanisms of cellular differentiation are likely to be prerequisite to future successes. The current research into replacing the RPE monolayer is briefly discussed with reference to our experiences comparing IPE and RPE cells in an in vitro environment.

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Vision Improvement in Retinal Degeneration Patients by Implantation of Retina Together with Retinal Pigment Epithelium

Cited by 224 publications

References 45 publications

Stem Cells for Retinal Replacement Therapy

Stem Cells for Retinal Replacement Therapy

Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures

Replacement of the RPE monolayer

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