Abstract
End-stage age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are two major retinal degenerative (RD) conditions that result in irreversible vision loss. Permanent eye damage can also occur in battlefields or due to accidents. This suggests there is an unmet need for developing effective strategies for treating permanent retinal damages. In previous studies, co-grafted sheets of fetal retina with its retinal pigment epithelium (RPE) have demonstrated vision improvement in rat retinal disease models and in patients, but this has not yet been attempted with stem-cell derived tissue. Here we demonstrate a cellular therapy for irreversible retinal eye injuries using a “total retina patch” consisting of retinal photoreceptor progenitor sheets and healthy RPE cells on an artificial Bruch’s membrane (BM). For this, retina organoids (ROs) (cultured in suspension) and polarized RPE sheets (cultured on an ultrathin parylene substrate) were made into a co-graft using bio-adhesives [gelatin, growth factor-reduced matrigel, and medium viscosity (MVG) alginate]. In vivo transplantation experiments were conducted in immunodeficient Royal College of Surgeons (RCS) rats at advanced stages of retinal degeneration. Structural reconstruction of the severely damaged retina was observed based on histological assessments and optical coherence tomography (OCT) imaging. Visual functional assessments were conducted by optokinetic behavioral testing and superior colliculus electrophysiology. Long-term survival of the co-graft in the rat subretinal space and improvement in visual function were observed. Immunohistochemistry showed that co-grafts grew, generated new photoreceptors and developed neuronal processes that were integrated into the host retina. This novel approach can be considered as a new therapy for complete replacement of a degenerated retina.
Highlights
Age-related macular degeneration (AMD) and retinitis pigmentosa (RP) lead to a profound loss of vision in millions worldwide
These include expression of markers for progenitors of photoreceptors, glia, ganglion cells, bipolar, horizontal, amacrine, and Müller cells, similar to what we have shown in previous publications for the CSC-14 cell line (McLelland et al, 2018; Lin et al, 2020) and for the cone-rod homeobox gene (CRX)-green fluorescent protein (GFP) cell line (Xue et al, 2021)
More extensive data have been published about the CSC-14-human embryonic stem cell(s) (hESCs)-derived retina organoid (RO) (McLelland et al, 2018)
Summary
Age-related macular degeneration (AMD) and retinitis pigmentosa (RP) lead to a profound loss of vision in millions worldwide. Many of these patients require replacement of both retinal pigment epithelium (RPE) and photoreceptors (PRs). Y. et al, 2021); cell transplantation has demonstrated positive effects which are considered to be mostly due to the introduction of neuroprotective growth factors released into the retina
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