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Brian C Gilger, Terete Borras, Matthew Hirsch; Ocular transduction following suprachoroidal space AAV vector administration in small and large animal models. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):259.
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© ARVO (1962-2015); The Authors (2016-present)
Clinical ocular gene therapy mediated by adeno-associated virus (AAV) vectors has restored vision with varied genetic diseases. AAV vector are administered by primarily subretinal (SR), and to a lesser extent intravitreal (IVit), injections. These routes are not ideal as they are invasive, associated with adverse complications, and result in either localized (SR) or inefficient (IVit) vector transduction. In contrast, the suprachoroidal space (SCS), as a potential site for ocular gene therapy, is an attractive administration route as delivery to this space is minimally invasive and avoids substantial barriers, such as the tear film, surface epithelium, conjunctival lymphatics, and the sclera. Additionally, because the SCS is adjacent to the entire choroid, AAV vector administration into the SCS has the potential to provide targeted drug delivery to tissues within the ocular posterior segment, such as the choroid and retina. Therefore, the purpose of this work is to generate an “AAV Road Map” for ocular transduction in which capsid serotypes are correlated to specific ocular tissue transduction.
A comprehensive panel of the individual AAV serotypes 1-11 packaged with a self-complementary egfp reporter was administered to the SCS in WT mouse by microinjection, and New Zealand White rabbit models using microneedles. AAV vector transduction was monitored by live imaging for GFP fluorescence and post-mortem by immunofluorescence on ocular sections. In the larger animal model, off target tissue transduction was monitored by Q-PCR and the neutralizing antibody response to the AAV capsid was evaluated as well.
In vivo ocular fundus imaging and ocular tissue section evaluation for GFP fluorescecence demonstrated serotype-dependent transduction efficiencies and, in some cases, widespread retinal transduction. The distribution of tissue transduction was serotype dependent. Vector dissemination from the ocular compartment and vector neutralizing antibody were low as evaluated in the large animal (rabbit) model.
Tissue transduction was serotype dependent and in some cases resulted in widespread retinal transduction after SCS adminstration. Therefore, AAV vector administration to the SCS may represent a safer drug delivery route with serotype dependent implications for the treatment of posterior ocular diseases.
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