A team of scientists based primarily at Moorfields Eye Hospital and University College London has performed a study implanting embryonic stem cell patches on to the retinas of two patients with age-related macular degeneration and demonstrated significant improvements in their vision. The early results of this were published in the March edition of Nature Biotechnology (da Cruz et al. 2018).
AMD is among the commonest causes of visual loss in developed countries and results from damage to the macula; the 5mm area of the retina (nerve tissue lining the inside of the eye) which is most densely packed with photosensitive rod and cone cells. Specifically, AMD is caused by damage to a layer of cells in the retina called the retinal pigment epithelium (RPE) which underlies and supports the rods and cones. AMD usually occurs in the 5th and 6th decade and manifests as progressive central visual loss resulting in difficulty recognising faces, reading and driving. While gene therapy strategies (usually using adeno-associated viruses) have delivered important early successes in rare monogenic retinal diseases like Leber congenital amaurosis and choroidaemia, stem cell approaches are more appropriate in degenerative conditions like AMD which result from multiple genetic and environmental risk factors.
In the study, human embryonic stem cells (hESCs) from the UK cell bank were expanded, differentiated into RPE and grown on a plastic membrane. An initial safety study involving the intraretinal injection of these cells in 80 mice confirmed that their persistence at 26 weeks with no resulting teratomas whereas the administration of undifferentiated hESCs did result in these tumours. The RPE patches were then delivered into the retinas of 10 pigs using a custom-designed delivery tool. This showed limited inflammation at the site comparable with controls which received a cell-free patch. Importantly there was no evidence of metastasis of hESCs to distant sites when multiple tissues were analysed by PCR- a very sensitive method for detecting specific DNA sequences.
The goal of the clinical trial was to demonstrate safety and efficacy of the patch as well as graft stability in the absence of long term systemic immunosuppression. The first two treated patients who had severe AMD showed that the grafts were still present at 12 months with some local migration of hESC-RPE cells to the surrounding areas. Significant improvements in visual acuity were observed in both patients using a variety of validated measures including best corrected visual acuity via the standard ETDRS letter-reading chart where the patients improved by 21 and 29 letters. One patient treated with a patch later experienced a retinal detachment. However this was limited, fully corrected with surgery and is a recognised complication of retinal surgery.
To contextualise this improvement, the current gold standard treatment for this disease is repeated intraocular injections of anti-VEGF therapies to prevent the growth of fragile retinal vessels which drive progression. The 2006 ANCHOR trial published in the New England Journal of Medicine (Brown et al. 2006) demonstrated mean improvements from baseline of 6 to 8 letters at 12 months in the anti-VEGF groups although these patients had milder disease than the two patients in this study.
A Japanese group has safely treated AMD patients using RPE cell sheets derived from induced pluripotent stem cells (iPSCs) but did not demonstrate improvement in visual acuity. (Mandai et al. 2017) The development of iPSCs has generally reduced the need for embryonic stem cells which are more controversial and difficult to obtain but the authors of this study point out that hESC patches can be prepared more quickly where disease is rapidly progessing.
In conclusion, results from the first two cases show that hESC-RPE patches appear safe and efficacious. Upcoming studies will shed more light on the maximal duration of benefit and whether it is possible for disease to re-emerge in the implanted patch and will give us greater safety data. If stem cell patches can be made cost-effective, they could become the new gold standard treatment for degenerative retinal diseases like AMD and diabetic retinopathy which are two of the commonest causes for blindness worldwide.
Brown, D. M., et al. (2006). “Ranibizumab versus verteporfin for neovascular age-related macular degeneration.” N Engl J Med 355(14): 1432-1444.
da Cruz, L., et al. (2018). “Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration.” Nat Biotechnol 36(4): 328-337.
Mandai, M., et al. (2017). “Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration.” N Engl J Med 376(11): 1038-1046.