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Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model

Author

Listed:
  • Ruchi Sharma

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Aman George

    (Pediatric, Developmental, & Genetic Ophthalmology Section, National Eye Institute, National Institutes of Health)

  • Malika Nimmagadda

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Davide Ortolan

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Barbosa-Sabanero Karla

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Zoya Qureshy

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Devika Bose

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Roba Dejene

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Genqing Liang

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Qin Wan

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Justin Chang

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Balendu Shekhar Jha

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Omar Memon

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Kiyoharu Joshua Miyagishima

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Aaron Rising

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • Madhu Lal

    (Research Governance Council, FDA)

  • Eric Hanson

    (Intramural Research Program, NIAMS, National Institutes of Health)

  • Rebecca King

    (Division of Preclinical Innovation, NCATS, National Institutes of Health)

  • Mercedes Maria Campos

    (Histology Core, National Eye Institute, National Institutes of Health)

  • Marc Ferrer

    (Division of Preclinical Innovation, NCATS, National Institutes of Health)

  • Juan Amaral

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

  • David McGaughey

    (Ophthalmic Genetics and Visual Functions Branch, National Eye Institute, National Institutes of Health)

  • Kapil Bharti

    (Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health)

Abstract

Age-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE) and atrophy of the RPE monolayer in advanced disease stages - leading to photoreceptor cell death and vision loss. Currently, there are no drugs that stop drusen formation or RPE atrophy in AMD. Here we provide an iPSC-RPE AMD model that recapitulates drusen and RPE atrophy. Drusen deposition is dependent on AMD-risk-allele CFH(H/H) and anaphylatoxin triggered alternate complement signaling via the activation of NF-κB and downregulation of autophagy pathways. Through high-throughput screening we identify two drugs, L-745,870, a dopamine receptor antagonist, and aminocaproic acid, a protease inhibitor that reduce drusen deposits and restore RPE epithelial phenotype in anaphylatoxin challenged iPSC-RPE with or without the CFH(H/H) genotype. This comprehensive iPSC-RPE model replicates key AMD phenotypes, provides molecular insight into the role of CFH(H/H) risk-allele in AMD, and discovers two candidate drugs to treat AMD.

Suggested Citation

  • Ruchi Sharma & Aman George & Malika Nimmagadda & Davide Ortolan & Barbosa-Sabanero Karla & Zoya Qureshy & Devika Bose & Roba Dejene & Genqing Liang & Qin Wan & Justin Chang & Balendu Shekhar Jha & Oma, 2021. "Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27488-x
    DOI: 10.1038/s41467-021-27488-x
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    Cited by:

    1. Sayan Ghosh & Ruchi Sharma & Sridhar Bammidi & Victoria Koontz & Mihir Nemani & Meysam Yazdankhah & Katarzyna M. Kedziora & Donna Beer Stolz & Callen T. Wallace & Cheng Yu-Wei & Jonathan Franks & Devi, 2024. "The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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