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P. Heiduschka, S. Julien, A. Günther, F. Ziemssen, S. Schultheiss, U. Schraermeyer; Rescue of Degenerating Photoreceptors in the RCS Rat by an AAV2/4-RPE65-Mertk Vector. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5192.
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The RCS rat with its mutation in the Mertk gene and therefore the loss of phagocytic function of the retinal pigment epithelium (RPE) is an established model for retinitis pigmentosa. We checked whether photoreceptors can be rescued from degeneration by the introduction of an intact copy of the rat Mertk gene by an adeno-associated viral vector.
We used an AAV2/4-RPE65-Mertk vector with a high specificity for RPE cells and a high effectiveness of Mertk expression. A solution of the vector (2 µl with 1.2x1011 vg/ml) was injected subretinally into the eyes of 13 20-day-old RCS rats. As a control, PBS alone was injected in three rats, and sham surgery or no treatment was performed in 14 rats. After one or two months, protective effects were evaluated by checking retinal function by electroretinography (ERG), inspection of the eyes by optical coherence tomography (OCT) as well as histological and ultrastructural evaluation of sections of the eyes.
Enhanced ERG amplitudes compared to the control eyes could be recorded in 8 out of 13 eyes injected with the AAV Mertk vector one month after the injection of the vector, and in 7 out of 10 eyes two months after the injection. Histological inspection of the eyes revealed a well-preserved photoreceptor layer, though restricted to a part of the eye, in 8 out of 12 eyes one month after the injection of the vector, and in 6 out of 8 eyes two months after the injection, whereas normal degeneration was found in 11 out of 13 eyes injected with PBS. Enhanced survival of photoreceptors was found in particular in those eyes where increased ERG amplitudes had been measured before. An increased thickness of the retina was also found by OCT, simultaneously with a decreased autofluorescence in the rescued area. Moreover, phagosomes could be detected in the RPE by electron microscopy two months after an injection of the vector.
We found that degenerating photoreceptors in the RCS rat can be rescued and their function can be preserved by a subretinal injection of an AAV Mertk vector. Further studies will target the issues of long-lasting effects and a broader distribution of the injected vector in the eye. These results encourage the search for a gene therapy for retinitis pigmentosa.
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