In situ regeneration of retinal pigment epithelium by gene transfer of E2F2: a potential strategy for treatment of macular degenerations


The retinal pigment epithelium (RPE) interacts closely with photoreceptors to maintain visual function. In degenerative diseases such as Stargardt disease and age-related macular degeneration, the leading cause of blindness in the developed world, RPE cell loss is followed by photoreceptor cell death. RPE cells can proliferate under certain conditions, suggesting an intrinsic regenerative potential, but so far this has not been utilised therapeutically. Here, we used E2F2 to induce RPE cell replication and thereby regeneration. In both young and old (2 and 18 month) wildtype mice, subretinal injection of non-integrating lentiviral vector expressing E2F2 resulted in 47% of examined RPE cells becoming BrdU positive. E2F2 induced an increase in RPE cell density of 17% compared with control vector-treated and 14% compared with untreated eyes. We also tested this approach in an inducible transgenic mouse model of RPE loss, generated through activation of diphtheria toxin-A gene. E2F2 expression resulted in a 10-fold increase in BrdU uptake and a 34% increase in central RPE cell density. Although in mice this localised rescue is insufficiently large to be demonstrable by electroretinography, a measure of massed retinal function, these results provide proof-of-concept for a strategy to induce in situ regeneration of RPE for the treatment of RPE degeneration.

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This work was supported by the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL, and also by Moorfields Eye Charity and RP Fighting Blindness. The authors gratefully acknowledge Anselm Kampik, Augenzentrum im Brienner Hof, Munich, Germany, for helpful discussions. The authors thank Nancy Joyce, Schepens Eye Research Institute, Harvard Medical School, Boston, USA, for providing the human E2F2 cDNA plasmid.

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Correspondence to R R Ali.

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UFOL is employee of F Hoffmann-La Roche Ltd. The remaning authors declare no conflict interest.

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Kampik, D., Basche, M., Luhmann, U. et al. In situ regeneration of retinal pigment epithelium by gene transfer of E2F2: a potential strategy for treatment of macular degenerations. Gene Ther 24, 810–818 (2017).

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