title: Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration.
abstract: Assessments of safety and efficacy are crucial before human ESC (hESC) therapies can move into the clinic. Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness. Here we show long-term functional rescue using hESC-derived RPE in both the RCS rat and Elov14 mouse, which are animal models of retinal degeneration and Stargardt, respectively. Good Manufacturing Practice-compliant hESC-RPE survived subretinal transplantation in RCS rats for prolonged periods (>220 days). The cells sustained visual function and photoreceptor integrity in a dose-dependent fashion without teratoma formation or untoward pathological reactions. Near-normal functional measurements were recorded at >60 days survival in RCS rats. To further address safety concerns, a Good Laboratory Practice-compliant study was carried out in the NIH III immune-deficient mouse model. Long-term data (spanning the life of the animals) showed no gross or microscopic evidence of teratoma/tumor formation after subretinal hESC-RPE transplantation. These results suggest that hESCs could serve as a potentially safe and inexhaustible source of RPE for the efficacious treatment of a range of retinal degenerative diseases.
authors.affiliation: Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.forename: Christopher
authors.initials: C
authors.lastname: Malcuit
authors.forename: Shaomei
authors.initials: S
authors.lastname: Wang
authors.forename: Sergej
authors.initials: S
authors.lastname: Girman
authors.forename: Peter
authors.initials: P
authors.lastname: Francis
authors.forename: Linda
authors.initials: L
authors.lastname: Lemieux
authors.forename: Robert
authors.initials: R
authors.lastname: Lanza
authors.forename: Raymond
authors.initials: R
authors.lastname: Lund
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D019295:Computational Biology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000637:transplantation; D015870:Gene Expression; D006801:Humans; D008268:Macular Degeneration / Q000628:therapy*; D051379:Mice; D025341:Principal Component Analysis; D051381:Rats; D012160:Retina / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods