A Cure for Blindness in Sight?

Posted on 2021-04-26

Retinal Pigment Epithelium (RPE) degeneration contributes to sight loss in approximately 200 million individuals worldwide. RPE is a single-layer epithelium located under the neurosensory retina, and it is essential for vision. Primary roles include the formation of the outer blood-retinal barrier, phagocytosis of shed photoreceptor outer segments (POSs), and the management of fluid, ion and nutrient transport. Research into RPE transplantation to restore RPE function offers a promising treatment for disorders such as age-related macular degeneration.

Human RPE stem cell-derived RPEs (hRPESC-RPEs) display key stem cell properties; including proliferation, self-renewal, and differentiation into multiple progeny. They offer a potentially unlimited, as well as human leukocyte antigen (HLA) matching, cell source capable of regenerating the RPE monolayer, with a reduced chance of immune rejection. hRPESC-RPE transplantation has previously been shown to restore vision in rat models of retinal dystrophy, and graft survival was observed for approximately 1 month in rabbit retina. In a recent trial, Liu, Z. et al. surgically transplanted hRPESC-RPE monolayers on polyethylene terephthalate (PET) under the macula of monkeys, in the first non-human primate (NHP) model. The grafts were non-invasively monitored by in vivo ophthalmic assessments over 3 months.

The main limitations of stem-cell derived transplantations are the uncertain survival of cells and the inherent risk of uncontrolled cell proliferation. Liu, Z. et al. used specific cell markers to measure the survival of hRPESC-RPE grafts in the NHP model. Cells were stained for, and positive for, the human-specific markers STEM121 (specific to human cytoplasmic protein) and TRA-1-85/CD147 (a cell surface determinant expressed on almost all human cell types); both markers are absent in native monkey RPE.

Post-transplantation, hRPESC-RPEs may undergo epithelial-mesenchymal transition (EMT) resulting in proliferative vitreoretinopathy or the formation of epiretinal membranes (ERMs). Liu, Z. et al. observed that at 3 months post-transplantation, the hRPESC-RPE graft did not express COL1A1 and αSMA, key markers for EMT; an encouraging sign that uncontrolled proliferation did not occur. The team also observed an absence of cleaved caspase-3 and Ki67, indicating that the transplanted cells were neither undergoing apoptosis, nor hyper-proliferating. 

The group demonstrated that, not only did the transplant support the existing healthy photoreceptors of the NHP model, the hRPESC-RPEs partially contributed to overall visual processes. To investigate functionality, grafts were co-stained with the apical RPE marker ezrin and the POS marker rhodopsin to assess phagocytosis; rhodopsin-positive puncta were observed underneath the apical membrane of hRPESC-RPE, suggesting outer segment phagocytosis and processing. Increased expression of RPE65 and CRALBP, two components critical for normal RPE function, at 3 months post-translation compared with pre-transplanted cultures further supported hRPESC-RPE functionality.

The trial concludes that hRPESC-RPEs grafts in a healthy NHP model are safe and stable. The cells successfully survived and functioned in vivo for at least 3 months post-transplantation in the presence of systemic immunosuppression, and they did not show the hallmarks of EMT. Though there is inevitably further research that needs to be conducted before human applications can be applied, the study nevertheless demonstrates the exciting feasibility of stem cell-replacement therapy as a treatment for macular degeneration and sight loss.

Further Reading:

Surgical Transplantation of Human RPE Stem Cell-Derived RPE Monolayers into Non-Human Primates with Immunosuppression

Transplants of Retinal Cells could Treat Blindness

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