title: Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies.
abstract: BACKGROUND
  Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients.
  
  
  METHODS
  In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50,000, 100,000, and 150,000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration).
  
  
  RESULTS
  There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardt's macular dystrophy.
  
  
  CONCLUSIONS
  The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement.
  
  
  BACKGROUND
  Advanced Cell Technology.
authors.affiliation: Jules Stein Eye Institute Retina Division, and David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address: schwartz@jsei.ucla.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Schwartz
authors.affiliation: Wills Eye Hospital and Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Regillo
authors.affiliation: Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.
authors.forename: Byron L
authors.initials: BL
authors.lastname: Lam
authors.affiliation: Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, MA, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Eliott
authors.affiliation: Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenfeld
authors.affiliation: Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.
authors.forename: Ninel Z
authors.initials: NZ
authors.lastname: Gregori
authors.affiliation: Jules Stein Eye Institute Retina Division, and David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hubschman
authors.affiliation: Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Davis
authors.affiliation: Jules Stein Eye Institute Retina Division, and David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Heilwell
authors.affiliation: Wills Eye Hospital and Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Spirn
authors.affiliation: Wills Eye Hospital and Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Maguire
authors.affiliation: Advanced Cell Technology, Marlborough, MA, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Gay
authors.affiliation: Advanced Cell Technology, Marlborough, MA, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Bateman
authors.affiliation: Jules Stein Eye Institute Retina Division, and David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Rosaleen M
authors.initials: RM
authors.lastname: Ostrick
authors.affiliation: Advanced Cell Technology, Marlborough, MA, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Morris
authors.affiliation: Advanced Cell Technology, Marlborough, MA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Vincent
authors.affiliation: Advanced Cell Technology, Marlborough, MA, USA.
authors.forename: Eddy
authors.initials: E
authors.lastname: Anglade
authors.affiliation: Storm Eye Institute, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Lucian V
authors.initials: LV
authors.lastname: Del Priore
authors.affiliation: Advanced Cell Technology, Marlborough, MA, USA. Electronic address: rlanza@advancedcell.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Lanza
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000637:transplantation*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008268:Macular Degeneration / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011788:Quality of Life; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000637:transplantation*; D000080362:Stargardt Disease; D016896:Treatment Outcome; D014792:Visual Acuity; D055815:Young Adult