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 patient-specific 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 naïve 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 Mfrp(rd6)/Mfrp(rd6) 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 Mfrp(rd6)/Mfrp(rd6) preclinical model suggests that this form of degeneration caused by MFRP mutations is a potential target for interventional trials.
authors.affiliation: Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, New York, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, New York, USA.
authors.forename: Wen-Hsuan
authors.initials: WH
authors.lastname: Wu
authors.affiliation: Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, New York, USA.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Hsu
authors.affiliation: Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Huy V
authors.initials: HV
authors.lastname: Nguyen
authors.affiliation: Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, New York, USA.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Tsai
authors.affiliation: Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, New York, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, New York, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nagasaki
authors.affiliation: Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Maumenee
authors.affiliation: Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, New York, USA.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Yannuzzi
authors.affiliation: 1] Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, New York, USA [2] New York-Presbyterian Hospital/Columbia University Medical Center, New York, New York, USA.
authors.forename: Quan V
authors.initials: QV
authors.lastname: Hoang
authors.affiliation: 1] Division of Molecular Genetics, Department of Pediatrics and Naomi Berrie Diabetes Center, Columbia University, New York, New York, USA [2] New York Stem Cell Foundation, New York, New York, USA.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Hua
authors.affiliation: New York Stem Cell Foundation, New York, New York, USA.
authors.forename: Dieter
authors.initials: D
authors.lastname: Egli
authors.affiliation: 1] New York-Presbyterian Hospital/Columbia University Medical Center, New York, New York, USA [2] Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Tsang
mesh_terms: D000818:Animals; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000821:virology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010641:Phenotype; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D012174:Retinitis Pigmentosa / Q000473:pathology / Q000628:therapy*; D055815:Young Adult; D000099274:Frizzled-Related Proteins
chemical_list: D003094:Collagen; D008565:Membrane Proteins; C487851:C1QTNF5 protein, human; C490110:MFRP protein, human; D000099274:Frizzled-Related Proteins