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M. Cordeiro, N. Wood, W. Cheung, S. Atwell, E. Kulikowski, L. Guo; Novel TGF-ß Gene Therapy Targeting the Optic Nerve Head (ONH) Is "Neuroprotective" in Experimental Glaucoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5510. doi: https://doi.org/.
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TGF-β is a key regulator in the healing response throughout the body, and is strongly implicated in the glaucomatous process at the ONH. Using a novel TGF-β antagonist with an AAV2 viral vector, TGF-β ShieldTM (Resverlogix, Canada), targeting TGF-β at the ONH, we have investigated whether modulation of the ONH response in experimental glaucoma was a possible treatment strategy.
30 DA rats with surgically-induced chronic ocular hypertension (OHT) randomly received sub-Tenon injections of either 0.0264 x1012 (High-dose TGF-β Shield or control AAV2) or 0.0132 x1012 (Low-dose TGF-β Shield or control AAV2) viral titres or untreated control (at least n = 4 per treatment) at the time of IOP elevation. DARC (detection of apoptosing retinal ganglion cells) imaging was performed at 3, 6 and 12 weeks after IOP elevation to assess RGC apoptosis in vivo, with histological analysis done thereafter.
High-dose TGF-β Shield significantly (p<0.05) reduced RGC apoptosis at all time points studied, with mean reduction levels of RGC apoptosis quantified as 66.9%, 54.8% and 55.0% at 3, 6 and 12 weeks respectively compared to control AAV2. Low-dose TGF-β Shield had a significant reduction in RGC apoptosis compared to control AAV2 only at 12 weeks (p<0.05) with mean reduction levels of 38.2%, 63.9%, and 82.1% at 3, 6 and 12 weeks respectively.
A single application of the TGF-β ShieldTM treatment at the ONH appears to have long-term effects and effectively inhibit RGC apoptosis induced in experimental glaucoma. These findings support the mechanical theory of glaucoma implicating retinal ganglion cell (RGC) axonal compression at the ONH as a mechanism of damage. As far as we are aware this is the first time that any therapy has been successfully targeted at the ONH. Furthermore, our results suggest that TGF-β modulation at the ONH may be a potential approach in the treatment of glaucomatous disease.
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