Retinal Pigment Epithelium Transplantation in a Non-human Primate Model for Degenerative Retinal Diseases

Abstract

Retinal pigment epithelial (RPE) transplantation holds great promise for the treatment of inherited and acquired retinal degenerative diseases. These conditions include retinitis pigmentosa (RP) and advanced forms of age-related macular degeneration (AMD), such as geographic atrophy (GA). Together, these disorders represent a significant proportion of currently untreatable blindness globally. These unmet medical needs have generated heightened academic interest in developing methods of RPE replacement. Among the animal models commonly utilized for preclinical testing of therapeutics, the non-human primate (NHP) is the only animal model that has a macula. As it shares this anatomical similarity with the human eye, the NHP eye is an important and appropriate preclinical animal model for the development of advanced therapy medicinal products (ATMPs) such as RPE cell therapy. This manuscript describes a method for the submacular transplantation of an RPE monolayer, cultured on a polyethylene terephthalate (PET) cell carrier, underneath the macula onto a surgically created RPE wound in immunosuppressed NHPs. The fovea-the central avascular portion of the macula-is the site of the greatest mechanical weakness during the transplantation. Foveal trauma will occur if the initial subretinal fluid injection generates an excessive force on the retina. Hence, slow injection under perfluorocarbon liquid (PFCL) vitreous tamponade is recommended with a dual-bore subretinal injection cannula at low intraocular pressure (IOP) settings to create a retinal bleb.

Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state

“…This enables RPE monolayers to readily adapt to the in vivo environment posttransplant, and perform RPE functions more readily, without requiring additional time for repolarization, unlike in RPE cell suspension transplants. Efficient RPE cell recovery from the explanted RPE scaffolds in our study was enabled using our published RPE monolayer transplant surgical technique ( 20 , 45 ). Thus, we were able to retrieve and sequence a total number of 2,460 transplanted RPE cells, compared to a recent study, whereby only 65 RPE cells were retrieved from subretinal RPE cell suspension transplant in two rabbits ( 14 ).…”

“…The retinotomy was enlarged with vertical vitreous scissors (Geuder). Preloaded bullet-shaped day 60 RPE monolayer implants (ESC-RPE, n = 3; iPSC-RPE, n = 3) were delivered subretinally using a custom-made device ( 45 , 58 ). All three transplantation surgeries for each RPE line were performed on the same day to ensure adherence to an exact 30-d period in the eye.…”

Stem cell-based therapy for myopic maculopathy: a new concept

“…A wide array of proangiogenic cytokines, such as VEGF, basic fibroblast growth factor (bFGF), and placental growth factor (PlGF), can be detected in the conditioned media of MSCs. Injection of the MSC media into murine ischemic limb markedly enhanced the limb's perfusion [215] . Due to decreased choroidal perfusion and hypoxia of sclera in highly myopic patients, the conditioned media of MSCs offers a good option to modify the hypoxic circumstance of sclera.…”

Changes of alpha-2-macroglobulin activity in tear fluid in experimental retinal pigment epithelium atrophy of rabbits

“…Для разработки метода пересадки РПЭ, помимо создания клеточной культуры, способной заменить пигментный эпителий, требуется воспроизвести адекватную модель атрофии РПЭ, доставить в область атрофии клетки и создать условия для их приживления. В последние годы с целью изучения данной патологии были предложены различные экспериментальные модели [6,7].…”