Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy

被引:109
作者
Tschernutter, M
Schlichtenbrede, FC
Howe, S
Balaggan, KS
Munro, PM
Bainbridge, JWB
Thrasher, AJ
Smith, AJ
Ali, RR
机构
[1] UCL, Inst Ophthalmol, Div Mol Therapy, London EC1V 9EL, England
[2] UCL, Inst Child Hlth, Mol Immunol Unit, London EC1V 9EL, England
关键词
retinitis pigmentosa; lentivirus; RCS rat; MERTK; retinal pigment epithelium;
D O I
10.1038/sj.gt.3302460
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Royal College of Surgeons (RCS) rat is a well-characterized model of autosomal recessive retinitis pigmentosa ( RP) due to a defect in the retinal pigment epithelium (RPE). It is homozygous for a null mutation in the gene encoding, a receptor tyrosine kinase found in RPE cells, that is required for phagocytosis of shed photoreceptor outer segments. The absence of Mertk results in accumulation of outer segment debris. This subsequently leads to progressive loss of photoreceptor cells. In order to evaluate the efficacy of lentiviral-mediated gene replacement therapy in the RCS rat, we produced recombinant VSV-G pseudotyped HIV-1-based lentiviruses containing a murine Mertk cDNA driven by a spleen focus forming virus ( SFFV) promoter. The vector was subretinally injected into the right eye of 10-day-old RCS rats; the left eye was left untreated as an internal control. Here, we present a detailed assessment of the duration and extent of the morphological rescue and the resulting functional benefits. We examined animals at various time points over a period of 7 months by light and electron microscopy, and electroretinography. We observed correction of the phagocytic defect, slowing of photoreceptor cell loss and preservation of retinal function for up to 7 months. This study demonstrates the potential of gene therapy approaches for the treatment of retinal degenerations caused by defects specific to the RPE and supports the use of lentiviral vectors for the treatment of such disorders.
引用
收藏
页码:694 / 701
页数:8
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