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Scott Ellis, Peter Widdowson, Katie Binley, T. Michael Nork, Paul Miller, Vlad Bantseev, Brian Christian, Kyriacos Mitrophanous, Stuart Naylor; Safety And Tolerability Of Retinostat®, A Lentiviral-vector Based Gene Therapy Product For The Treatment Of Wet Age-related Macular Degeneration, In Rabbits And Monkeys. Invest. Ophthalmol. Vis. Sci. 2011;52(14):488.
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Age-related macular degeneration (AMD) is a major cause of statutory blindness in the developed world is caused by the formation of aberrant blood vessels from the choroid. RetinoStat® is a new lentiviral-vector based gene therapy for the treatment of wet AMD that expresses the angiostatic proteins endostatin and angiostatin. Good laboratory practice regulatory studies in both rabbits and rhesus macaques were designed to examine the safety and tolerability of RetinoStat following a single subretinal administration.
RetinoStat was injected subretinally in the right eyes of 38 Dutch-belted rabbits and 6 Rhesus macaques of both sexes. An equal number of animals received an injection with formulation buffer. Ophthalmic examinations were performed using slit-lamp biomicroscopy, indirect ophthalmoscopy and applanation tonometry. Inflammation/ocular tolerability measures were recorded up to 6 months. Retinal function was assessed by full field electroretinography (ERG) and flash visual evoked cortical potentials (VEP). Histopathologic examination was performed periodically in rabbits and at 6 months post-dose in monkeys.
No overt toxicity associated with subretinally injected RetinoStat was observed clinically in the rabbits or monkeys. In all eyes of both treatment and control groups, retinal pigment epithelial (RPE) mottling was seen at the re-attached blebs. The level of inflammation following subretinal injection of RetinoStat in both species was negligible and returned to baseline within 3 weeks. Intraocular pressure remained unchanged. ERG/VEP recordings did not show any abnormal responses in eyes treated with RetinoStat. Detailed histopathological examination of the eyes at 3 days, 1 week, 1 month, 3 months and 6 months in the rabbits and at 6 months in the monkeys did not reveal any detrimental effects of RetinoStat.
Subretinal delivery of RetinoStat vector in Dutch-belted rabbits and Rhesus macaques was well tolerated, with no relevant associated toxicity and no evidence of long term adverse changes in global retinal function allowing further progress in human evaluation.
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