title: Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease.
abstract: OBJECTIVE
  StarGen is an equine infectious anemia virus (EIAV)-based lentiviral vector that expresses the photoreceptor-specific adenosine triphosphate (ATP)-binding cassette transporter (ABCA4) protein that is mutated in Stargardt disease (STGD1), a juvenile macular dystrophy. EIAV vectors are able to efficiently transduce rod and cone photoreceptors in addition to retinal pigment epithelium in the adult macaque and rabbit retina following subretinal delivery. The safety and biodistribution of StarGen following subretinal delivery in macaques and rabbits was assessed.
  
  
  METHODS
  Regular ophthalmic examinations, IOP measurements, ERG responses, and histopathology were carried out in both species to compare control and vector-treated eyes. Tissue and fluid samples were obtained to evaluate the persistence, biodistribution, and shedding of the vector following subretinal delivery.
  
  
  RESULTS
  Ophthalmic examinations revealed a slightly higher level of inflammation in StarGen compared with control treated eyes in both species. However, inflammation was transient and no overt toxicity was observed in StarGen treated eyes and there were no abnormal clinical findings. There was no StarGen-associated rise in IOP or abnormal ERG response in either rabbits or macaques. Histopathologic examination of the eyes did not reveal any detrimental changes resulting from subretinal administration of StarGen. Although antibodies to StarGen vector components were detected in rabbit but not macaque serum, this immunologic response did not result in any long-term toxicity. Biodistribution analysis demonstrated that the StarGen vector was restricted to the ocular compartment.
  
  
  CONCLUSIONS
  In summary, these studies demonstrate StarGen to be well tolerated and localized following subretinal administration.
authors.affiliation: Oxford BioMedica-UK Ltd., Oxford Science Park, Oxford, United Kingdom. k.binley@oxfordbiomedica.co.uk
authors.forename: Katie
authors.initials: K
authors.lastname: Binley
authors.forename: Peter
authors.initials: P
authors.lastname: Widdowson
authors.forename: Julie
authors.initials: J
authors.lastname: Loader
authors.forename: Michelle
authors.initials: M
authors.lastname: Kelleher
authors.forename: Sharifah
authors.initials: S
authors.lastname: Iqball
authors.forename: Georgina
authors.initials: G
authors.lastname: Ferrige
authors.forename: Jackie
authors.initials: J
authors.lastname: de Belin
authors.forename: Marie
authors.initials: M
authors.lastname: Carlucci
authors.forename: Diana
authors.initials: D
authors.lastname: Angell-Manning
authors.forename: Felicity
authors.initials: F
authors.lastname: Hurst
authors.forename: Scott
authors.initials: S
authors.lastname: Ellis
authors.forename: James
authors.initials: J
authors.lastname: Miskin
authors.forename: Alcides
authors.initials: A
authors.lastname: Fernandes
authors.forename: Paul
authors.initials: P
authors.lastname: Wong
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.forename: Christopher
authors.initials: C
authors.lastname: Bergstrom
authors.forename: Thomas
authors.initials: T
authors.lastname: Aaberg
authors.forename: Jiong
authors.initials: J
authors.lastname: Yan
authors.forename: Jian
authors.initials: J
authors.lastname: Kong
authors.forename: Peter
authors.initials: P
authors.lastname: Gouras
authors.forename: Annick
authors.initials: A
authors.lastname: Prefontaine
authors.forename: Mark
authors.initials: M
authors.lastname: Vezina
authors.forename: Martin
authors.initials: M
authors.lastname: Bussieres
authors.forename: Stuart
authors.initials: S
authors.lastname: Naylor
authors.forename: Kyriacos A
authors.initials: KA
authors.lastname: Mitrophanous
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D001826:Body Fluids / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D004860:Infectious Anemia Virus, Equine / Q000235:genetics*; D007429:Intraocular Pressure; D008253:Macaca mulatta; D008268:Macular Degeneration / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011817:Rabbits; D000080362:Stargardt Disease; D014018:Tissue Distribution; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D049452:Green Fluorescent Proteins
keywords: gene therapy; lentivirus; photoreceptors