Recent Progress in Photoreceptor Cell-Based Therapy for Degenerative Retinal Disease

Abstract

Age-related macular degeneration and retinitis pigmentosa are degenerative retinal diseases that cause severe vision loss. Early clinical trials involving transplantation of photoreceptors as treatment for these conditions are underway. In this review, we summarize recent progress in the field of photoreceptor transplantation, including some pertinent results regarding photoreceptor manufacture, photoreceptor transplantation, mechanisms of donor-host cell integration such as material transfer and photoreceptor transplant immunology. We conclude by proposing several approaches that may provide a rational basis for selecting a vision restoration strategy (eg, donor-host synapse formation vs donor-host nanotube formation) and improved transplant efficiency.

Keywords: cell transplantation; embryonic stem cells; geographic atrophy; induced pluripotent stem cells; macular degeneration; retina; retinal pigment epithelium; retinitis pigmentosa.

Graphical Abstract

Figure 1.

Variability in green fluorescent protein (GFP) patterning is dependent on mutant background. In contrast to the restricted outer nuclear layer (ONL)-GFP signal observed in wild-type background at 21 days following transplant (top), the NRL^−/− hybrid-cone only recipient (middle) exhibits robust GFP signal that extends to Müller glia and bipolar neurons. In contrast, no GFP material exchange has been reported in the degenerating retina (bottom), suggesting a photoreceptor-to-photoreceptor modality of intercellular communication. Reproduced with permission from Nickerson et al.

Figure 2.

Schematic illustration of the honeycomb-shaped microscaffold showing (a) a tilted top view, (b) a tilted bottom view, (c) a cross-sectional view, and (d) a top view, respectively. The hexagonal prism-shaped cell capture wells (white in color) are designed to have a large volume (ie, 40 μm in depth and 48 μm in length for each side of the hexagon) for capturing and retaining both RPE and PR cells in the wells, and the cylinder-shaped fluid channels (orange in color) are tailored to be narrow enough (ie, ~4 μm) to prevent the seeded cells from migrating through the channels while still supporting cell functions during scaffold degradation. Reproduced with permission from Lee et al.

Figure 3.

Green fluorescent protein (GFP)-labeled acceptor photoreceptors are connected to transplanted donor photoreceptors via cell protrusions. Top: Maximum intensity projection of a confocal micrograph of a cryostat section from a Nrl^−/− recipient retina 21 days after transplantation with Nrl::GFP donor photoreceptors, showing protrusions (pink arrows) connecting donor and acceptor photoreceptors. Bottom: 3D reconstruction of confocal microscopy images of whole-mounted retinas from C57BL6/J recipients 21 days after transplantation with Nrl::GFP donor photoreceptors (top layer) shows that donor and GFP + acceptor photoreceptors appear to be attached via protrusions. 3D reconstruction shows protrusions (pink arrows) and GFP labeling in acceptor cells. Reproduced with permission from Ortin-Martinez et al.

Figure 4.

Representative scanning electron micrograph images with digitally enhanced microphotographs of cultured P8 Nrl.Gfp+/+ photoreceptors. Red arrows indicate photoreceptor nanotube connections between neighboring photoreceptors, while blue arrows indicate broken photoreceptor nanotube connections (N = 3 cultures). Scale bar = 5 μm. Reproduced with permission from Kalargyrou et al.

Figure 5.

Lymphocyte graft immune reaction (LGIR) tests detected subclinical rejection in repeated MHC-mismatched transplantation. Left photographs: In vivo images of the color fundus photographs, FAG, and OCT images of the eyes that received a second transplantation 3 months after the first transplantation. Orange circles indicate graft areas. Each OCT image shows the sectional view of the line indicated by the white arrow on the color fundus image. Right graphs: Line plotting results for LGIR tests following transplantation. Vertical lines indicate post/pre-transplantation LGIR scores. Horizontal lines indicate months after transplantation. Magenta arrows show the time points when the post/pre-LGIR scores were above 2-fold in 2 or more cell types after transplantation (subclinical rejection). LGIR test, lymphocyte graft immune reaction test; DD, differentiation day; FAG, fluorescein angiography; OCT, optical coherence tomography. Scale bars: 1 mm. Reproduced with permission from: Uyama et al.

Figure 6.

Cross-sectional optical coherence tomography (OCT) with angio flow (denoted in red) and 3 × 3 mm en face optical coherence tomography angiography (OCTA) of the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC). Top—images from a 28-year-old man with severe center involving retinitis pigmentosa (RP1 mutation). There is diffuse loss of vasculature in the DCP and CC. Middle—images from an 18-year-old woman with mild center sparing retinitis pigmentosa (IMPDH1 mutation). The vasculature in SCP, DCP, and CC appear grossly preserved. Bottom—images from a 44-year-old male control without retinitis pigmentosa. Dotted yellow lines denote artifacts from segmentation errors (top) and a vitreous floater (bottom). Reproduced with permission from Ong et al.