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Cecile Fortuny, Leah Byrne, Deniz Dalkara, Trevor Lee, Bilge Esin Ozturk; AAV-mediated Combination Therapy of Neurotrophic and Anti-Apoptotic Factors in a Mouse Model of Inherited Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2746.
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© ARVO (1962-2015); The Authors (2016-present)
Many inherited retinal degenerative diseases, such as retinitis pigmentosa, result in blindness as a result of photoreceptor cell death. Since numerous different genetic mutations are involved in these disorders, it is advantageous to develop general therapies that promote photoreceptor survival regardless of the underlying mutation. In a mouse model, we investigated the therapeutic potential of a combination cell survival therapy using intravitreal injections of two serotypes of adeno-associated virus (AAV) to express a secreted trophic factor, glial-derived neurotrophic factor (GDNF) in Müller glia, and an anti-apoptotic factor, X-linked inhibitor of apoptosis protein (XIAP), in photoreceptors.
C57BL/6 mice were co-injected intravitreally with different concentrations of two engineered adeno-associated virus (AAV) variants: ShH10, an AAV6 variant which selectively targets Müller glia, and 7m8, an AAV2 variant capable of extensive photoreceptor transduction from the vitreous. Fluorophores mCherry and GFP were respectively expressed under the control of the CAG promoter and the photoreceptor-specific rhodopsin promoter (Rho). Fundus fluorescence imaging was performed before eyes were enucleated four weeks post-injection. Dark reared rd10 mice were injected intravitreally in one eye at p15 with (1) 7m8.Rho.XIAP, (2) ShH10.CAG.GDNF or (3) a mix of both XIAP/GDNF. The contralateral control eyes were sham injected with PBS. Electroretinograms (ERGs) were recorded to quantify rescue of rod and cone-mediated responses at p45 and p55.
Imaging of retinal sections showed that, at a variety of concentration ratios, co-injection of 7m8 and ShH10 led to simultaneous and strong expression of GFP in photoreceptors and mCherry in Müller glia. Co-injection of vectors encoding XIAP and GDNF led to a significant increase in amplitude of the ERG A-wave and B-wave.
We showed that co-injected 7m8 and ShH10 remained cell-specific and transduced their intended targeted cells without significant competitive inhibition. The combination therapy co-delivering XIAP and GDNF showed a significant effect in slowing the progression of retinal degeneration in a rodent model of retinitis pigmentosa and represents a promising gene therapy approach to treat inherited diseases.
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