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Brian Kevany, Susie Suh, Jennings Lu, Linas Padegimas, Krzysztof Palczewski, Timothy Miller; Novel AAV Capsids Demonstrate Strong Retinal Expression in Non-Human Primates After Intravitreal Administration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2900.
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The eye represents a unique opportunity for the use of gene therapy due to its immune privileged status, relatively small size and the availability of non-invasive imaging to monitor safety and efficacy. Historically, AAV administration to the eye has been performed by subretinal injection between the neural retina and underlying retinal pigmented epithelium (RPE). While this method provides the benefit of positioning the vector directly next to its cellular target, it requires a retinal detachment, possibly damaging the retina, as well as an operating room and trained retinal surgeon, likely limiting the broad applicability of any therapy. Ideally, a therapy that is administered directly into the vitreous of the eye would provide a safer and likely more applicable approach. Here, we describe the identification of a novel AAV capsid that provides robust expression in both the inner and outer retina after intravitreal administration in both mice and non-human primates (NHPs).
EGFP transgene cassettes, under the control of a modified chicken beta actin promoter, were packaged into our novel AAV capsids. AAVs were administered to either wild type C57BL6 mice at 2.5E+10 vg/eye or non-human primates at 1.5E+12 vg/eye. Animals were imaged in-life using scanning laser ophthalmoscopy and optical coherence tomography and upon completion of the studies eyes were removed, processed for histological examination and analyzed by immunohistochemistry (IHC).
We demonstrate broad expression in photoreceptors, bipolar cells and RPE in wild type mice that shows a time dependent increase in expression. Intravitreal administration to NHPs showed strong foveal expression as well as wide-spread expression in the peripheral retina within four weeks post-treatment. NHP retinal expression was highest in the photoreceptor cell layer, found in both rod and cone cells, bipolar, ganglion and RPE cells.
Due to its broad cellular tropism, this engineered AAV capsid is clinically translatable to treat a wide range of retinal dystrophies, including both inherited and acquired forms. Importantly, this novel AAV can be administered using a relatively safe method that can be administered in an out-patient retinal clinic, allowing broader availability of any new therapy to previously under-treated communities.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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