Pharmaceuticals 2012, 5(5), 447-459; doi:10.3390/ph5050447
Article

The Signalling Role of the avβ5-Integrin Can Impact the Efficacy of AAV in Retinal Gene Therapy

Received: 20 February 2012; in revised form: 3 April 2012 / Accepted: 19 April 2012 / Published: 2 May 2012
(This article belongs to the Special Issue Gene Therapy)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract: Sub-retinal injection of the common AAV2 pseudotypes frequently results in strong transduction of the retinal pigment epithelium (RPE) as well as the retina itself. This has been of benefit to date in human clinical trials using AAV, where the disease target is in the RPE. However, many mutations predisposing to retinal disease are located in the photoreceptor cells, present in the neural retina and not the RPE; in this case the sub-retinal injection route may cause an effective “loss” of therapeutic AAV to the RPE. The avβ5 integrin receptor is highly expressed on the apical surface of the RPE, and is essential to the daily phagocytosis of the outer segment tips of photoreceptor cells. The transduction efficiency of AAV was tested in the retinas of β5−/− mice lacking this receptor and showing defects in photoreceptor outer segment phagocytosis. Following sub-retinal injection of AAV2/5-eGFP, fluorescence was found to be stronger and more widespread in the neural retina of β5−/− mice compared to wild-types with greatly reduced fluorescence in the RPE. Increased levels of the phagocytic signalling protein MFG-E8, the ligand for the avβ5 integrin receptor, is found to have a moderate inhibitory effect on AAV transduction of the retina. However the opposite effect is found when only the integrin-binding domain of MFG-E8, the RGD (Arginine-Glycine-Aspartic acid) domain, was increased. In this case RGD enhanced AAV-mediated retinal transduction relative to RPE transduction. These results are presented for their relevance for the design of AAV-based retinal gene therapy strategies strategies targeting retinal/photoreceptor cells.
Keywords: adeno-associated virus; retinal gene therapy; MFG-E8; avβ5 integrin; photoreceptor outer segments
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MDPI and ACS Style

Cronin, T.; Chung, D.C.; Yang, Y.; Nandrot, E.F.; Bennett, J. The Signalling Role of the avβ5-Integrin Can Impact the Efficacy of AAV in Retinal Gene Therapy. Pharmaceuticals 2012, 5, 447-459.

AMA Style

Cronin T, Chung DC, Yang Y, Nandrot EF, Bennett J. The Signalling Role of the avβ5-Integrin Can Impact the Efficacy of AAV in Retinal Gene Therapy. Pharmaceuticals. 2012; 5(5):447-459.

Chicago/Turabian Style

Cronin, Therese; Chung, Daniel C.; Yang, Ying; Nandrot, Emeline F.; Bennett, Jean. 2012. "The Signalling Role of the avβ5-Integrin Can Impact the Efficacy of AAV in Retinal Gene Therapy." Pharmaceuticals 5, no. 5: 447-459.

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