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P. Widdowson, S. Ellis, K. Binley, M. Nork, P. Miller, V. Bantseev, R. McCulloh, O. Kan, S. Naylor; Ocular Tolerance of an Eiav Based Lentiviral Vector Treatment for Neovascular Age-Related Macular Degeneration (Retinostat®) in Rabbits and Nonhuman Primate Models. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3104.
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Age-related macular degeneration (AMD) is a major cause of blindness in the developed world. We are currently developing a novel equine infectious anemia virus (EIAV)-based lentiviral gene therapy called RetinoStat®, for the treatment of wet-AMD that is designed to express the potent angiostatic proteins endostatin (End) and angiostatin (Ang). These studies were designed to examine toleration of rabbits and NHPs to subretinally delivered RetinoStat.
Subretinally-delivered (100µL) RetinoStat (transgene expression driven by the constitutive CMV promoter) was examined at two dose strengths (1.1x105 and 1.1x106 transducing units (TU)/eye) in the Dutch-belted pigmented rabbit and at the low dose in the rhesus macaque. Regular ophthalmic examinations were performed using slit-lamp biomicroscopic apparatus and ocular toleration measures were recorded. After 1 month, the animals were euthanized and the levels of End and Ang measured in aqueous and vitreous and in 6mm punches of the retina/choroid in the region of vector administration.
The inflammation observed with the low dose RetinoStat was transient (mild to moderate aqueous and vitreous cell scores between 3 and 8 days after dosing by slit-lamp microscopy) and did not differ from that observed with formulation buffer in both rabbits and macaques. The inflammation scores in a 10-fold higher dose in rabbit eyes were greater than those measured with formulation buffer (moderate to severe vitreous cell scores beyond 8 days after dosing by slit-lamp microscopy). However, neither dose produced overt toxicity in either the rabbit or macaques. Measurement of the End and Ang in the vitreous of the rabbits was not significantly different between the high and lower doses demonstrating that lowering the vector strength did not negatively impact on transgene expression. Comparisons of End and Ang under the constitutive CMV promoter and the retinal pigment epithelial cell specific VMD2 promoter demonstrated greater protein production with the CMV promoter in both the retina and vitreous.
Subretinal delivery of RetinoStat vector in rabbits and macaques was well tolerated at vector concentrations of 1.1x105 TU/eye. End and Ang were detected in the retina and vitreous. Detailed GLP toxicology and biodistribution studies are now underway in both rabbits and macaques to prepare progression to clinical trials.
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