AAV-Mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa

• Published in: Molecular therapy Vol. 8; no. 2; pp. 188 - 195
• Main Authors: Smith, Alexander J, Schlichtenbrede, Frank C, Tschernutter, Marion, Bainbridge, James W, Thrasher, Adrian J, Ali, Robin R
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2003; Elsevier Limited
• Subjects: adeno-associated virus; Animals; c-Mer Tyrosine Kinase; Dependovirus - genetics; Disease Models, Animal; Electroretinography; Eye - metabolism; Eye - pathology; Gene therapy; Genetic Therapy; Humans; Kinases; MERTK gene; Mice; Mutation; Photoreceptor Cells - metabolism; Photoreceptor Cells - pathology; Photoreceptors; Proto-Oncogene Proteins; Rats; RCS rat; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Retina; retinal pigment epithelium; retinitis pigmentosa; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - metabolism; Retinitis Pigmentosa - pathology; Retinitis Pigmentosa - therapy; Time Factors; Transgenes - genetics; Vectors (Biology); Viruses; retinitis pigmentosa; gene therapy; RCS rat; adeno-associated virus; retinal pigment epithelium; MERTK gene
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/S1525-0016(03)00144-8

In the Royal College of Surgeons (RCS) rat, the retinal pigment epithelium (RPE) cannot phagocytose the outer segment discs that are continually shed from photoreceptors. The resulting accumulation of debris in the subretinal space leads to a progressive loss of photoreceptors. The defect results from a mutation in the Mertk gene, which is normally expressed in the RPE. Mertk is a receptor tyrosine kinase, involved in the binding of photoreceptor debris. Mutations in MERTK have also been described in patients with retinitis pigmentosa (RP). Here we demonstrate that subretinal injection of recombinant adeno-associated virus (AAV) expressing the murine Mertk gene can significantly prolong photoreceptor cell survival in the RCS rat. Electroretinographic analysis of treated eyes showed that functional photoreceptors were still present at 9 weeks, when there is virtually no activity in untreated control eyes. Histological analysis of treated eyes revealed a decrease in the amount of debris in the subretinal space, suggesting that RPE function was restored. Moreover, 9 weeks after treatment the number of photoreceptors was 2.5-fold higher in treated than in control eyes. This study provides strong support for the development of AAV-mediated gene therapy for RP caused by mutations in the MERTK gene.