@article{a388fee724b94c5e9c21a2eac4afc456,
title = "Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells",
abstract = "Stargardt retinopathy is an inherited form of macular degeneration caused by mutations in gene ABCA4 and characterized by the accumulation of lipid-rich deposits in the retinal pigment epithelium (RPE), RPE atrophy, and photoreceptor cell death. Inadequate mechanistic insights into pathophysiological changes occurring in Stargardt RPE have hindered disease treatments. Here, we show that ABCA4 knockout and induced pluripotent stem cell-derived RPE (STGD1-iRPE) from patients with Stargardt differentiate normally but display intracellular lipid and ceramide deposits reminiscent of the disease phenotype. STGD1-iRPE also shows defective photoreceptor outer segment (POS) processing and reduced cathepsin B activity—indicating higher lysosomal pH. Lipid deposits in STGD1-iRPE are lowered by increasing the activity of ABCA1, a lipid transporter, and ABCA4 ortholog. Our work suggests that ABCA4 is involved in POS and lipid handling in RPE cells and provides guidance for ongoing gene therapy approaches to target both RPE and photoreceptor cells for an effective treatment.",
keywords = "ABCA1, ABCA4, AMD, RPE, lipid deposits, lipid handling, lysosome dysfunction, phagocytosis defects, retinal degeneration",
author = "Mitra Farnoodian and Devika Bose and Vladimir Khristov and Susaimanickam, {Praveen Joseph} and Savitri Maddileti and Indumathi Mariappan and Mones Abu-Asab and Maria Campos and Rafael Villasmil and Qin Wan and Arvydas Maminishkis and David McGaughey and Francesca Barone and Gundry, {Rebekah L.} and Riordon, {Daniel R.} and Boheler, {Kenneth R.} and Ruchi Sharma and Kapil Bharti",
note = "Funding Information: This research was supported by the Intramural Research Program of the NIH, National Eye Institute, Fulbright-Nehru Doctoral Research Fellowship (#2118/DR/2016-2017), Department of Biotechnology, Government of India (#BT/01/COE/06/02/10), and NIH funding (#HL134010 to R.L.G). In addition, the authors thank Aparna Lakkaraju (UCSF, CA, USA) for helpful discussions and feedback; Robert Farris and Jennifer Kielczewski (NEI Biological Imaging Core), Harshad D. Vishwasrao, and Jiamin Liu (Advanced Imaging & Microscopy Resource, NIH), Zhihong Yang and Alan Remaley (NHLBI, Lipoprotein Metabolism Section), Guan Bin, Davide Ortolan, and Pushkar Sathe for technical assistance; Jizhong Zou and Kaari Linask (NHLBI-iPSC core) for generating two ABCA4−/− iPSC lines; and Subhadra Jalali and Chitra Kannabiran (LVPEI, Hyderabad, India) for genetic screening of patients with Stargardt and identification of ABCA4 mutations. The authors declare no competing interests. Funding Information: This research was supported by the Intramural Research Program of the NIH , National Eye Institute , Fulbright-Nehru Doctoral Research Fellowship (# 2118/DR/2016-2017 ), Department of Biotechnology, Government of India (# BT/01/COE/06/02/10 ), and NIH funding (# HL134010 to R.L.G). In addition, the authors thank Aparna Lakkaraju (UCSF, CA, USA) for helpful discussions and feedback; Robert Farris and Jennifer Kielczewski (NEI Biological Imaging Core), Harshad D. Vishwasrao, and Jiamin Liu (Advanced Imaging & Microscopy Resource, NIH), Zhihong Yang and Alan Remaley (NHLBI, Lipoprotein Metabolism Section), Guan Bin, Davide Ortolan, and Pushkar Sathe for technical assistance; Jizhong Zou and Kaari Linask (NHLBI-iPSC core) for generating two ABCA4 −/− iPSC lines; and Subhadra Jalali and Chitra Kannabiran (LVPEI, Hyderabad, India) for genetic screening of patients with Stargardt and identification of ABCA4 mutations. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = nov,
day = "8",
doi = "10.1016/j.stemcr.2022.10.001",
language = "English (US)",
volume = "17",
pages = "2438--2450",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "11",
}