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

Nat Commun. 2021 Dec 15;12(1):7293. doi: 10.1038/s41467-021-27488-x.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Alleles
  • Aminocaproic Acid / pharmacology*
  • Complement Factor H / genetics
  • Complement Factor H / metabolism
  • Drug Evaluation, Preclinical
  • Humans
  • Induced Pluripotent Stem Cells / drug effects*
  • Induced Pluripotent Stem Cells / metabolism
  • Macular Degeneration / drug therapy*
  • Macular Degeneration / genetics
  • Macular Degeneration / metabolism
  • Models, Biological
  • Phenotype
  • Pyridines / pharmacology*
  • Pyrroles / pharmacology*
  • Retinal Pigment Epithelium / drug effects*
  • Retinal Pigment Epithelium / metabolism


  • 3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine
  • CFH protein, human
  • Pyridines
  • Pyrroles
  • Complement Factor H
  • Aminocaproic Acid