@article{83ba1eaa67cd4d5fb27af73510e1b20d,
title = "Gene therapy in patient-specific stem cell lines and a preclinical model of retinitis pigmentosa with membrane frizzled-related protein defects",
abstract = "Defects in Membrane Frizzled-related Protein (MFRP) cause autosomal recessive retinitis pigmentosa (RP). MFRP codes for a retinal pigment epithelium (RPE)-specific membrane receptor of unknown function. In patientspecific induced pluripotent stem (iPS)-derived RPE cells, precise levels of MFRP, and its dicistronic partner CTRP5, are critical to the regulation of actin organization. Overexpression of CTRP5 in naive human RPE cells phenocopied behavior of MFRP-deficient patient RPE (iPS-RPE) cells. AAV8 (Y733F) vector expressing human MFRP rescued the actin disorganization phenotype and restored apical microvilli in patient-specific iPS-RPE cell lines. As a result, AAV-treated MFRP mutant iPS-RPE recovered pigmentation and transepithelial resistance. The efficacy of AAV-mediated gene therapy was also evaluated in Mfrprd6/ Mfrprd6 mice-an established preclinical model of RP-and long-term improvement in visual function was observed in AAV-Mfrp-treated mice. This report is the first to indicate the successful use of human iPS-RPE cells as a recipient for gene therapy. The observed favorable response to gene therapy in both patient-specific cell lines, and the Mfrprd6/Mfrprd6 preclinical model suggests that this form of degeneration caused by MFRP mutations is a potential target for interventional trials.",
author = "Yao Li and Wu, {Wen Hsuan} and Hsu, {Chun Wei} and Nguyen, {Huy V.} and Tsai, {Yi Ting} and Lawrence Chan and Takayuki Nagasaki and Maumenee, {Irene H.} and Yannuzzi, {Lawrence A.} and Hoang, {Quan V.} and Haiqing Hua and Dieter Egli and Tsang, {Stephen H.}",
note = "Funding Information: We thank Sherry Shen, Scott Smemo, Lewis Brown, Kristy Brown, and members of the Bernard & Shirlee Brown Glaucoma laboratories for sharing ideas, cell lines, antisera, and equipment, and for critically reviewing the manuscript, especially, Kelly Davis; and supports from The Macula Foundation Inc, Justin A Manus, Kobi and Nancy Karp. Imaging and animal facilities are supported by the National Institute of Health Core grant 5P30EY019007 and NCI Core grant 5P30CA013696 and unrestricted funds from Research to Prevent Blindness, Columbia University, New York and University of Illinois, Chicago, USA. S.H.T. is a member of the RD-CURE Consortium and is supported by Tistou and Charlotte Kerstan Foundation, NIH R01EY018213, the Research to Prevent Blindness Physician-Scientist Award, the Schneeweiss Stem Cell Fund, New York State (N09G-302 and N13G-275), and the Foundation Fighting Blindness New York Regional Research Center Grant (C-NY05-0705-0312), the Joel Hoffman Fund, Gale and Richard Siegel Stem Cell Fund, Charles Culpeper Scholarship, Laszlo Bito and Olivia Carino Foundation, Irma T. Hirschl Charitable Trust, Bernard and Anne Spitzer Stem Cell Fund, Professor Gertrude Rothschild Stem Cell Foundation, and Gebroe Family Foundation. H.V.N. is supported by the RPB Medical Student Fellowship.",
year = "2014",
doi = "10.1038/mt.2014.100",
language = "English (US)",
volume = "22",
pages = "1688--1697",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "9",
}