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

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, Omar Memon, Kiyoharu Joshua Miyagishima, Aaron Rising, Madhu Lal, Eric Hanson, Rebecca King, Mercedes Maria Campos, Marc Ferrer, Juan Amaral, David McGaughey and Kapil Bharti ()
Additional contact information
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

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27488-x

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