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

Sharma, Ruchi; George, Aman; Nimmagadda, Malika; Ortolan, Davide; Karla, Barbosa-Sabanero; Qureshy, Zoya; Bose, Devika; Dejene, Roba; Liang, Genqing; Wan, Qin; Chang, Justin; Jha, Balendu Shekhar; Memon, Omar; Miyagishima, Kiyoharu Joshua; Rising, Aaron; Lal, Madhu; Hanson, Eric; King, Rebecca; Campos, Mercedes Maria; Ferrer, Marc

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. Age-related macular degeneration is characterized by lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE). Here the authors report an in vitro iPSC-RPE model for AMD that recapitulates drusen and RPE atrophy, and identify two drugs that reduce drusen deposits and restore RPE epithelial phenotype.

MACULAR degeneration; PHENOTYPES; VISION disorders; HIGH throughput screening (Drug development); PHOTORECEPTORS; RHODOPSIN; DOPAMINE receptors

Nature Communications, 2021, Vol 12, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-021-27488-x