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L. Guo, T. E. Salt, W. Cheung, F. RussoMarie, M. E. Cheetham, S. E. Moss, F. W. Fitzke, M. F. Cordeiro; Long-Term Effects of Combination versus Single Agent Therapy Targeting Amyloid-ß in Glaucoma Treatment. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5495.
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We have recently demonstrated that amyloid-ß (Aß) is associated with glaucoma, and that its targeting significantly reduces retinal ganglion cell (RGC) apoptosis in experimental glaucoma. In this study, we have investigated long-term effects of combination verses single agent therapy targeting Aß in glaucoma treatment.
Using a rat model of chronic ocular hypertension (OHT), we intravitreally administered single, dual and triple combinations of three different agents targeting Aß pathway at the time of surgical IOP elevation: monoclonal anti-Aß antibody (Aßab (0.5mg/ml, n=5), Congo red (CR, 1.46mg/ml, n=5), ß-secretase inhibitor (ßSI, 10µg/ml, n=5), and vehicle control (n=5). For combination therapy (Triple (Aßab+CR+ßSI), Dual1(Aßab+CR), Dual2 (Aßab+ßSI)) individual treatments were combined with the same doses as in the monotherapy. Animals were imaged for RGC apoptosis at 3, 8 and 16 weeks after IOP elevation using our novel DARC (Detection of Apoptosing Retinal Cells) imaging method and then sacrificed for histology.
All combination therapies targeting different aspects of Aß pathway showed a reduction of RGC apoptosis at 3, 8 and 16 weeks compared to vehicle control although this was only significant at 3 weeks (p<0.05). Triple therapy was found to be the most effective combination regimen in prevention of RGC death, consistently reducing levels of RGC apoptosis by 84%, 66% and 75% at 3, 8 and 16 weeks compared to 74%, 58% and 51% with Aßab alone (which was the most effective monotherapy), although this effect was only statistically significant at 3 weeks (p<0.05). Dual therapies showed no statistical difference from Aßab alone or control at all the time points observed.
Combination treatments targeting different stages of amyloid-ß pathway appear more effective than single agent treatment in reducing RGC apoptosis in experimental glaucoma. However, this is only significant at 3 weeks after IOP elevation. We attribute the lack of a long-term effect to the fact that treatment was only given as a single application at the time of IOP elevation. We plan to shortly report on the effects of repeated applications of combination therapy.
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