Transduction of Photoreceptors With Equine Infectious Anemia Virus Lentiviral Vectors: Safety and Biodistribution of StarGen for Stargardt Disease

Autor: Alcides Fernandes, Jiong Yan, Kyriacos A. Mitrophanous, Paul Wong, Martin Bussieres, James Miskin, Diana Angell-Manning, S. Iqball, Stuart Naylor, Julie Loader, Thomas M. Aaberg, Peter Widdowson, Jackie de Belin, Rando Allikmets, Mark Vezina, Jiong Kong, Michelle Kelleher, Marie Carlucci, Katie Binley, Scott Ellis, Peter Gouras, Annick Prefontaine, C. Bergstrom, Georgina Ferrige, Felicity Hurst
Rok vydání: 2013
Předmět:
Male
Pathology
medicine.medical_specialty
genetic structures
Genetic enhancement
Blotting
Western
Genetic Vectors
Green Fluorescent Proteins
Cytomegalovirus
Gene Expression
ABCA4
Enzyme-Linked Immunosorbent Assay
Transfection
Polymerase Chain Reaction
Viral vector
Equine infectious anemia
Macular Degeneration
Transduction
Genetic
Electroretinography
medicine
Animals
Stargardt Disease
Tissue Distribution
Intraocular Pressure
Retinal pigment epithelium
biology
medicine.diagnostic_test
Articles
Genetic Therapy
Macular degeneration
medicine.disease
biology.organism_classification
Macaca mulatta
Virology
eye diseases
Body Fluids
Stargardt disease
medicine.anatomical_structure
biology.protein
ATP-Binding Cassette Transporters
Female
Rabbits
sense organs
Infectious Anemia Virus
Equine
Photoreceptor Cells
Vertebrate
Zdroj: Investigative Opthalmology & Visual Science. 54:4061
ISSN: 1552-5783
DOI: 10.1167/iovs.13-11871
Popis: 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.
Databáze: OpenAIRE
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