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A. Bemelmans, C. Kostic, S.V. Crippa, D. Hornfeld, M. Tekaya, W.W. Hauswirth, J. Lem, M.W. Seeliger, A. Wenzel; Lentiviral–Mediated Gene Transfer of Rpe65 in Mouse Models of Leber Congenital Amaurosis: Effects on Cone Degeneration and Function . Invest. Ophthalmol. Vis. Sci. 2006;47(13):847.
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The retinal pigment epithelium–specific protein RPE65 is responsible for the isomerization and the regeneration of the photopigment occurring during the retinoid visual cycle. In humans, RPE65 mutations lead to Leber congenital amaurosis (LCA) or early onset severe retinal dystrophy. The proof of feasibility of gene therapy has already been established in animal models of RPE65 deficiency, but the status of cone photoreceptors, although crucial for human high acuity and day vision, has not been investigated in detail so far.
To address this question, we have constructed a lentiviral vector (LV–RPE65) to transfer the mouse Rpe65 cDNA in the retinal pigment epithelium of Rpe65 knockout mice, a model for LCA in which cones degenerate quickly.
We show that subretinal delivery of LV–RPE65 leads to sustained expression of RPE65. Assessment for retinal function by recording of the electroretinogram response demonstrates that Rpe65 gene transfer restores the activity of both rod and cone photoreceptors. We use different cone–specific markers to study the effect of Rpe65 gene transfer on the survival of cone photoreceptors. This provides evidence that early treatment, i.e. by administration of LV–RPE65 at postnatal day 5, leads to robust cone protection, while treatment at a later time fails to prevent degeneration.
We provide evidence that Rpe65 gene transfer targeting the retinal pigment epithelium rescues the function of cone photoreceptors and prevents their degeneration in models of RPE65 deficiency. This is of particular importance for the treatment of humans, in whom high acuity and day vision rely on cone photoreceptors.
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