title: Long-term effects of intravitreal injection of GMP-grade bone-marrow-derived CD34+ cells in NOD-SCID mice with acute ischemia-reperfusion injury.
abstract: OBJECTIVE
  To determine long-term safety of intravitreal administration of good manufacturing practice (GMP)-grade human bone-marrow-derived CD34(+) cells in NOD-SCID (nonobese diabetic-severe combined immunodeficiency) mice with acute retinal ischemia-reperfusion injury, a model for retinal vasculopathy.
  
  
  METHODS
  Acute ischemia-reperfusion injury was induced in the right eye of adult NOD-SCID mice (n = 23) by transient elevation of intraocular pressure. Seven days later, 12 injured eyes and 5 normal contralateral eyes were injected each intravitreally with 5 × 10(4) CD34(+) cells isolated under GMP conditions from a healthy human donor bone marrow using an immunomagnetic cell isolation system. The remaining 11 injured eyes were not treated and served as controls. Mice were euthanized 1 day, 4 months, and 8 months later. Both eyes were enucleated and examined by immunohistochemical analysis and hematoxylin and eosin staining. Among mice followed for 8 months, electroretinography (ERG) was performed on both eyes before euthanization. All major organs were examined grossly and histologically after serial sectioning.
  
  
  RESULTS
  Immunohistochemical staining 4 months after injection showed detectable CD34(+) cells in the retinal vasculature. ERG at 8 months after CD34(+) cell injection showed signals that were similar in untreated eyes. Histology of the enucleated eyes injected with CD34(+) cells showed no intraocular tumor or abnormal tissue growth after 8 months. Histologic analysis of all major organs showed no abnormal proliferation of human cells.
  
  
  CONCLUSIONS
  Intravitreal administration of GMP-grade human bone-marrow-derived CD34(+) cells appears to be well tolerated long-term in eyes with acute retinal ischemic injury. A clinical trial will start to further explore this therapy.
authors.affiliation: Department of Ophthalmology and Vision Science, University of California Davis Eye Center, Sacramento, CA 95817, USA. susanna.park@ucdmc.ucdavis.edu
authors.forename: Susanna S
authors.initials: SS
authors.lastname: Park
authors.forename: Sergio
authors.initials: S
authors.lastname: Caballero
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bauer
authors.forename: Bradley
authors.initials: B
authors.lastname: Shibata
authors.forename: Alan
authors.initials: A
authors.lastname: Roth
authors.forename: Paul G
authors.initials: PG
authors.lastname: Fitzgerald
authors.forename: Krisztina I
authors.initials: KI
authors.lastname: Forward
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Jeannine
authors.initials: J
authors.lastname: McGee
authors.forename: David G
authors.initials: DG
authors.lastname: Telander
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.forename: Jan A
authors.initials: JA
authors.lastname: Nolta
mesh_terms: D000208:Acute Disease; D000818:Animals; D018952:Antigens, CD34; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology*; D004596:Electroretinography; D005500:Follow-Up Studies; D006085:Graft Survival; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D058449:Intravitreal Injections; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D012164:Retinal Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D033581:Stem Cell Transplantation / Q000379:methods*; D013997:Time Factors; D014183:Transplantation, Heterologous
chemical_list: D018952:Antigens, CD34