PURPOSE: 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.
PURPOSE: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: A Martínez-Mir; E Paloma; R Allikmets; C Ayuso; T del Rio; M Dean; L Vilageliu; R Gonzàlez-Duarte; S Balcells Journal: Nat Genet Date: 1998-01 Impact factor: 38.330
Authors: F P Cremers; D J van de Pol; M van Driel; A I den Hollander; F J van Haren; N V Knoers; N Tijmes; A A Bergen; K Rohrschneider; A Blankenagel; A J Pinckers; A F Deutman; C B Hoyng Journal: Hum Mol Genet Date: 1998-03 Impact factor: 6.150
Authors: O Grüter; C Kostic; S V Crippa; M-T R Perez; L Zografos; D F Schorderet; F L Munier; Y Arsenijevic Journal: Gene Ther Date: 2005-06 Impact factor: 5.250
Authors: R Allikmets; N Singh; H Sun; N F Shroyer; A Hutchinson; A Chidambaram; B Gerrard; L Baird; D Stauffer; A Peiffer; A Rattner; P Smallwood; Y Li; K L Anderson; R A Lewis; J Nathans; M Leppert; M Dean; J R Lupski Journal: Nat Genet Date: 1997-03 Impact factor: 38.330
Authors: Katie Binley; Peter S Widdowson; Michelle Kelleher; Jackie de Belin; Julie Loader; Georgina Ferrige; Marie Carlucci; Margaret Esapa; Daniel Chipchase; Diana Angell-Manning; Scott Ellis; Kyriacos Mitrophanous; James Miskin; Vlad Bantseev; T Michael Nork; Paul Miller; Stuart Naylor Journal: Hum Gene Ther Date: 2012-08-01 Impact factor: 5.695
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