title: cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness.
abstract: Immunologically-matched, induced pluripotent stem cell (iPSC)-derived photoreceptor precursor cells have the potential to restore vision to patients with retinal degenerative diseases like retinitis pigmentosa. The purpose of this study was to develop clinically-compatible methods for manufacturing photoreceptor precursor cells from adult skin in a non-profit cGMP environment. Biopsies were obtained from 35 adult patients with inherited retinal degeneration and fibroblast lines were established under ISO class 5 cGMP conditions. Patient-specific iPSCs were then generated, clonally expanded and validated. Post-mitotic photoreceptor precursor cells were generated using a stepwise cGMP-compliant 3D differentiation protocol. The recapitulation of the enhanced S-cone phenotype in retinal organoids generated from a patient with NR2E3 mutations demonstrated the fidelity of these protocols. Transplantation into immune compromised animals revealed no evidence of abnormal proliferation or tumor formation. These studies will enable clinical trials to test the safety and efficiency of patient-specific photoreceptor cell replacement in humans.
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Wiley
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Burnight
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: DeLuca
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Kristin R
authors.initials: KR
authors.lastname: Anfinson
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Cranston
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Kaalberg
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Penticoff
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Louisa M
authors.initials: LM
authors.lastname: Affatigato
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Mullins
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.affiliation: Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Budd A
authors.initials: BA
authors.lastname: Tucker
mesh_terms: D000328:Adult; D000818:Animals; D001766:Blindness / Q000209:etiology / Q000473:pathology* / Q000628:therapy; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009940:Organoids / Q000378:metabolism* / Q000637:transplantation; D057093:Orphan Nuclear Receptors / Q000235:genetics; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology* / Q000378:metabolism; D012162:Retinal Degeneration / Q000151:congenital / Q000473:pathology* / Q000628:therapy; D012867:Skin / Q000166:cytology / Q000378:metabolism; D014182:Transplantation, Autologous
chemical_list: C403073:NR2E3 protein, human; D057093:Orphan Nuclear Receptors; D006152:Cyclic GMP