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David L. Simons, Sanford L. Boye, William W. Hauswirth, Samuel M. Wu; Gene Therapy Prevents Photoreceptor Death in a Bardet-Biedl Syndrome Mouse Model. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5654.
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© ARVO (1962-2015); The Authors (2016-present)
Patients with Bardet-Biedl Syndrome (BBS) experience severe retinal degeneration as a result of impaired transport processes within the photoreceptors. To date, there is no effective treatment for BBS-associated retinal degeneration, and affected patients become legally blind by the average age of 16 years. Our goal was to develop a viral gene therapy treatment that could prevent rod photoreceptor degeneration in the Bbs4-null mouse model.
We generated pseudotyped self-complementary AAV2/5 virions containing hemagglutinin-tagged mouse Bbs4 driven by the mouse opsin promoter. Bbs4-null mice were treated with AAV-BBS4 by subretinal injection in the temporal hemiretina at 2 weeks of age and control eyes received either AAV-GFP or no injection. Transgene expression was analyzed by Western blot and immunohistochemistry. Mice were followed longitudinally by electroretinogram (ERG) to assess retinal function, and histology was performed at various late time points.
Injection of AAV-BBS4 produced a full-length (59 kDa) protein product that localized to the photoreceptor inner segment. At 12 weeks of age, retinal regions treated with AAV-BBS4 contained significantly fewer photoreceptors with mislocalized rhodopsin when compared to untreated regions of the same retina (p < .01). At 16 weeks, treated rods had outer segments morphologically similar to those of wild-type rods, while outer segments of untreated rods had degenerated beyond recognition. Cell counting in these eyes revealed a localized area of thick outer nuclear layer (4-6 nuclei per ONL column) near the site of AAV-BBS4 injection, while distant regions had continued to degenerate (1-2 nuclei per column). Analysis of the ERG a-wave indicated that the rod photoresponse had significantly larger amplitude and higher sensitivity in treated versus control eyes (p = .003 at 8 wks, p < .0001 at 12 and 16 wks).
Subretinal injection of our AAV vector results in Bbs4 protein expression in the inner segment that can rescue intra-cellular transport and prevent photoreceptor death in the Bbs4-null retina. Our findings suggest for the first time that BBS-associated retinal degeneration can be treated.
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