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F.C. Schlichtenbrede, A.J. Smith, M. Tschernutter, A.J. Thrasher, J.W. Bainbridge, R.R. Ali; Long Term Preservation of Retinal Function in the RCS Rat Model of Retinitis Pigmentosa following Lentivirus-mediated Gene Transfer of the Mertk Gene . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3584.
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Purpose: The Royal College of Surgeons (RCS) rat is a well characterised model of human retinal dystrophy due to a defect in the retinal pigment epithelium (RPE). It is homozygous for a null mutation in the Mertk gene which encodes a receptor tyrosine kinase normally expressed in the RPE. Its absence results in a failure to phagocytose outer segment discs shed by photoreceptor cells. The resulting accumulation of debris in the subretinal space causes a progressive loss of photoreceptor cells. In this study we used recombinant lentivirus expressing a murine Mertk gene to slow the retinal degeneration significantly and preserve retinal function. Methods: Recombinant lentivirus expressing the murine Mertk gene under the control of a SFFV promotor was injected subretinally into the right eye of 12 RCS rats on post natal day 10. The effect of treatment was analysed histologically using semithin light microscopy at different time points and electroretinography (ERG) was used to assess functional changes over time. ERGs of treated rats were recorded at regular intervals over a period of 7 months. The untreated contralateral eyes served as internal control. Results: Electroretinographic analysis showed a significant increase in b-wave amplitude as compared to the untreated side. This effect was first noted 6 weeks after treatment and persisted for up to 7 months. In the untreated contralateral eye b-wave amplitudes decreased rapidly after 2 months to only residual activity. Histological analysis of treated eyes showed a decrease in the amount of subretinal debris and significantly higher numbers of photoreceptor cells. Conclusions: Lentivirus mediated gene therapy slows photoreceptor cell loss and preserves retinal function over a time course of 7 months in the RCS rat. These results support the utility of gene therapy approaches for treatment of inherited retinopathies.
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