Cellular regeneration strategies for macular degeneration: past, present and future

Abstract

Despite considerable effort and significant therapeutic advances, age-related macular degeneration (AMD) remains the commonest cause of blindness in the developed world. Progressive late-stage AMD with outer retinal degeneration currently has no proven treatment. There has been significant interest in the possibility that cellular treatments may slow or reverse visual loss in AMD. A number of modes of action have been suggested, including cell replacement and rescue, as well as immune modulation to delay the neurodegenerative process. Their appeal in this enigmatic disease relate to their generic, non-pathway-specific effects. The outer retina in particular has been at the forefront of developments in cellular regenerative therapies being surgically accessible, easily observable, as well as having a relatively simple architecture. Both the retinal pigment epithelium (RPE) and photoreceptors have been considered for replacement therapies as both sheets and cell suspensions. Studies using autologous RPE, and to a lesser extent, foetal retina, have shown proof of principle. A wide variety of cell sources have been proposed with pluripotent stem cell-derived cells currently holding the centre stage. Recent early-phase trials using these cells for RPE replacement have met safety endpoints and hinted at possible efficacy. Animal studies have confirmed the promise that photoreceptor replacement, even in a completely degenerated outer retina may restore some vision. Many challenges, however, remain, not least of which include avoiding immune rejection, ensuring long-term cellular survival and maximising effect. This review provides an overview of progress made, ongoing studies and challenges ahead.

Fig. 1

A 76-year-old female patient presenting with dry AMD. First seen in 2013 with a visual acuity of logMAR 0.3 and small areas of paracentral RPE atrophy with surrounding drusen (a). Her vision slowly deteriorated to logMAR 1.0 over 3 years with increasing central geographic atrophy (b). Progression of central outer retinal atrophy shown on spectral domain optical coherence tomography (SDOCT) (c–f)

Fig. 2

Schematic diagram illustrating normal retina contrasted with the changes observed in dry AMD

Fig. 3

Potential multiple and overlapping modes of action of cellular therapies for AMD

Fig. 4

77-year-old female patient presenting with large submacular haemorrhage secondary to acute wet AMD (a). She initially underwent subretinal haemorrhage displacement surgery with vitrectomy, subretinal tissue plasminogen activator and ranibizuamb and air that although successful in terms of haemorrhage displacement revealed a large submacular scar (colour image (b), and SDOCT (c). The patient then underwent subretinal choroidal neovascular membrane removal, and peripheral large RPE/choroidal graft with a 200 degree temporal retinotomy. Postoperative appearance (d), with corresponding autofluorescent image showing uniform normal autofluorescence (e) and SDOCT with a perfused choroidal appearance visible (f)

Fig. 5

A 78-year-old male patient presenting with large submacular haemorrhage and extensive choroidal neovascular membrane in his right eye (a), having already lost vision in his left eye with an established disciform scar (b). Patient underwent macular relocation surgery with a 360 degree peripheral retinotomy and CNVM removal, and subsequent counter rotation surgery with visual improvement (c). Note scar (white arrow) from previous CNVM now eccentric to fovea

Fig. 6

Schematic diagram showing the sources, and retinal differentiation potential of human pluripotent stem cells. Embryonic stem cells are derived from the inner cell mass of a pre-implantation embryo. Pluripotency can be induced in adult somatic stem cells by the delivery of key transcription factors that reprogramme the cells (delivered in illustration by non-integrating Sendai viruses)

Fig. 7

Retinal organoids with adjacent RPE 3D differentiation from human pluripotent stem cells. Optic vesicles with lamination (a). b–d show a diagrammatic representation of the laminated area with schematic antibody labelling, adjacent to actual antibody-stained sections. b Photoreceptors labelled with CRX (green) and Recoverin (red), c photoreceptors, Recoverin (red), and retinal ganglion cells, HuC/D (green), d Muller glia (green)

Fig. 8

A 45-year-old male patient with Stargardt’s macular dystrophy with symmetrical atrophic maculae (a, b). Patient underwent vitrectomy with subretinal injection of a suspension of embryonic stem-cell-derived retinal pigment epithelial cells with an injection point superonasal to the foveal centre (c). (Injection point shown by black asterisk, area of subretinal bleb produced outlined by solid black line, with small subretinal air bubble indicated by white arrow: note image is intraoperative view with superior retina shown inferiorly). Nine-month postoperative appearance shows areas of subretinal pigment in the area of the original injection (white circle) (d)

Fig. 9

66-year-old male patient who developed a large macular hole with a previous macular involving retinal detachment. Despite a large diameter internal limiting membrane peel at the initial retinal reattachment surgery, the patient had a persisting macular hole after otherwise successful surgery (a, b: ILM peel area shown as black line). The patient underwent a free autologous transplantation of a patch of retina from just above the superotemporal arcade which was positioned within the macular hole rim. The day 1 postoperative appearance is shown in (c), and SDOCT at 2 weeks (d) and 6 weeks (e). Note the disorganised inner retina within the graft site but more normal appearing outer retina. SDOCT at 6 weeks following silicone oil removal showing an intact ellipsoid line (f.) Autofluorescent image taken at 6 weeks following oil removal (g) showing visible autofluorescence centrally. The patient displayed fixation over the graft with a visual acuity of logMAR 0.8