Otx2-Genetically Modified Retinal Pigment Epithelial Cells Rescue Photoreceptors after Transplantation

Abstract

Inherited retinal degenerations are blinding diseases characterized by the loss of photoreceptors. Their extreme genetic heterogeneity complicates treatment by gene therapy. This has motivated broader strategies for transplantation of healthy retinal pigmented epithelium to protect photoreceptors independently of the gene causing the disease. The limited clinical benefit for visual function reported up to now is mainly due to dedifferentiation of the transplanted cells that undergo an epithelial-mesenchymal transition. We have studied this mechanism in vitro and revealed the role of the homeogene OTX2 in preventing dedifferentiation through the regulation of target genes. We have overexpressed OTX2 in retinal pigmented epithelial cells before their transplantation in the eye of a model of retinitis pigmentosa carrying a mutation in Mertk, a gene specifically expressed by retinal pigmented epithelial cells. OTX2 increases significantly the protection of photoreceptors as seen by histological and functional analyses. We observed that the beneficial effect of OTX2 is non-cell autonomous, and it is at least partly mediated by unidentified trophic factors. Transplantation of OTX2-genetically modified cells may be medically effective for other retinal diseases involving the retinal pigmented epithelium as age-related macular degeneration.

A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models

“…Only two of them showed a quantitative analysis of the thickness of the retina (or a retinal cell layer). Both studies showed an increased effect on the thickness of the ONL in the group receiving an RPE transplantation [35,41].…”

“…Subgroup analysis was not conducted for awave amplitudes because the subgroups contained too few studies in order to draw meaningful conclusions (less than 4 studies per subgroup remained). For the meta-analysis of ERG b-wave amplitude, twelve [25,29,30,32,33,35,[39][40][41]44,45,49] studies reporting 42 experiments were included, of which 30 experiments were performed in rats and 12 in mice. See Supplementary 1 for all study characteristics of the individual studies.…”

“…and additional statistics data (individual Hedges' g, lower-and upper limits) can be found in Table S6. Sixteen studies [26][27][28]31,[34][35][36][37][38][39][41][42][43][46][47][48] reporting 96 experiments were included in the meta-analysis. Ninety-one studies were performed in rats and five in mice.…”

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

“…The construct should be then validated by analyzing the expression of the two transgenes after transient transfection and viral infection of cells in vitro. This presents no difficulty for RdCVF that is expressed under the control of a ubiquitous promoter, but requires more effort for RdCVFL that is regulated by a cone-specific promoter [137].…”

“…Interestingly, this model can be used to measure cone function using optometry, a behavior assay that relies on head tracking movement that is proportional to acuity and contrast sensitivity [164]. The effect of the treatment of rd10 is evaluated by several temporal sequences of electroretinogram (ERG) measurements of cone function by photopic and flicker ERG and optometry assays [103,111,137]. At the end of each experiment, the density of the cones is measured using e-conome after the sacrifice of the animals [165].…”