Investigative Ophthalmology & Visual Science Cover Image for Volume 62, Issue 8
June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Safe and immune-tolerant 'designer' RPE cells towards the treatment of age-related macular degeneration
Author Affiliations & Notes
  • Sabiha Hacibekiroglu
    Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
  • Eric Jong
    Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
    Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
  • Jean Tang
    Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
    Department of Physiology, University of Toronto, Toronto, Ontario, Canada
  • Tatiana Oussenko
    Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
  • Margaret Ho
    Terrence Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada
    Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
  • Molly S Shoichet
    Terrence Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada
    Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
  • Valerie Wallace
    Krembil Research Institute, Toronto, Ontario, Canada
    Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada
  • Peter Kertes
    Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
    Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada
  • Peng Yan
    Kensington Eye Institute, Toronto, Ontario, Canada
    Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada
  • Andras Nagy
    Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
    Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
  • Footnotes
    Commercial Relationships   Sabiha Hacibekiroglu, None; Eric Jong, None; Jean Tang, None; Tatiana Oussenko, None; Margaret Ho, None; Molly Shoichet, CA Patent # 2,784,847 (P), EP Patent # 2512516 (P), US Patent # 8,980,248 (P); Valerie Wallace, None; Peter Kertes, Alcon (F), Allergan (C), ArcticDx (I), Bayer (F), Bayer (C), Novartis (F), Novartis Nobility (C), Roche (C); Peng Yan, None; Andras Nagy, PanCELLa (S), SINAI HEALTH SYSTEM (P)
  • Footnotes
    Support  Fighting Blindness Canada Foundation, Canadian Research Chair, Medicine by Design (University of Toronto)
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 3281. doi:
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      Sabiha Hacibekiroglu, Eric Jong, Jean Tang, Tatiana Oussenko, Margaret Ho, Molly S Shoichet, Valerie Wallace, Peter Kertes, Peng Yan, Andras Nagy; Safe and immune-tolerant 'designer' RPE cells towards the treatment of age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2021;62(8):3281.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Frequent anti-VEGF injections and use of immunosuppressive drugs during RPE cell therapy can cause severe side effects. Also, the fear of tumorigenicity of grafted cells remains an issue. We test the hypothesis that cells, grafted into a diseased eye, expressing our local acting anti-VEGF biologics, ‘VEGF Sticky-trap’, with FailSafeTM and immune cloaking technologies, is safe and controllable as a long-term treatment option for AMD. This approach combines the cells’ positive therapeutic effect with that of local acting biologics, avoiding potentially harmful side effects.

Methods : In a mouse model of AMD, we have grafted engineered human RPE to replace the lost cells in the recipient’s eye that a) produce a drug-inducible, local acting anti-VEGF biologic (VEGF Sticky-trap, PMID: 24705878) and b) control cell growth by introducing a suicide switch to the cell’s genome (FailSafeTM, PMID: 30429614). The RPE cells generated in vitro from hES cells were further modified to make them “invisible” (iACT StealthTM, PMID: 31417198) to the immune system (cloaked cells), or not (uncloaked cells). To assess the efficacy, safety and toxicology of all genetic modifications, cells (cloaked and uncloaked) were injected in the subretinal space (40,000 cells per eye) and subcutaneously (either 1 million cells per flank or 100,000 cells intradermal in ear pinnae) in albino BL6 mice. Immune-compromised NSG mice served as a control and cell survival and efficacy was followed through life eye imaging or BLI imaging.

Results : We have demonstrated the function of all three genome altering systems (FailSafeTM, iACT Stealth and VEGF Sticky-trap) separately, in pilot studies and are moving forward to a pre-clinical phase with small (mouse) and large animal models (rabbit, pig) to test in cell therapy settings. Thus far we have demonstrated, in vitro and in vivo (in mice), that cells survive up to 10 months in subretinal spaces and that each genetic modification continues to function in tandem.

Conclusions : Immuno-cloaking is essential to avoid graft rejection and/or immunosuppressive drugs, while tight regulation of cell proliferation (FailSafeTM system) and drug-induced VEGF Sticky-trap expression was demonstrated. No adverse events were reported in mice receiving genetically modified cells. We expect our genome edited therapeutic cells to advance the development of novel and improved therapies for AMD and beyond.

This is a 2021 ARVO Annual Meeting abstract.

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