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Michel Janicot, Kathy Hasenbach, Tine Van Bergen, Lieve K M Moons, Ingeborg Stalmans, Katja Wosikowski; Efficacy of ISTH0036, a Potent and Selective Antisense Oligonucleotide Targeting Transforming Growth Factor beta 2 (TGF-β2) Isoform, in Different Ocular Disease Preclinical Models. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1278. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
ISTH0036 is a 14-mer phosphorothioate Locked Nucleic Acid- (LNA) modified antisense oligonucleotide gapmer, targeting TGF-β2 mRNA. It was shown to effectively and potently downregulate target mRNA in a dose-dependent manner in relevant cell-based assays, as well as leading to target engagement in anterior eye segment tissues upon intravitreal administration. The aim of the presented study was to evaluate the therapeutic potential of ISTH0036 in murine models of glaucoma filtration surgery (GFS) and laser-induced choroidal neovascularization (CNV) following intra-ocular administration.
Either Intracameral or intravitreal injections with ISTH0036, relevant scrambled control oligonucleotide or saline were performed in C75Bl/6 mice on day 0 and day 14 after GFS (trabeculectomy). CNV was induced in mice by placing 3 laser spots using a 532 nm laser. Intravitreal injection of either ISTH0036, relevant scrambled control oligonucleotide or saline was administered directly after laser procedure. Treatment outcome was studied by clinical investigation of the bleb in the GFS model every other day until day 28, whereas analysis of inflammation on day 5 (CD45) and angiogenesis on day 14 (FITC-dextran) was performed in the CNV model.
In the GFS model, upon intracameral administration (and to a lesser extent, intravitreal injection), ISTH0036 was able to significantly increase bleb area, as compared to the control oligonucleotide and saline treated eyes. Analysis of bleb area showed that ISTH0036 significantly prolonged bleb survival. In the CNV model, intravitreal administration of ISTH0036 was able to significantly reduce the process of angiogenesis, as compared to saline- and control oligonucleotide-treated eyes. On day 5 after laser, no difference could be detected on the inflammatory process after ISTH0036 treatment versus saline or control oligonucleotide.
We have clearly demonstrated in both GFS and CNV murine models that ISTH0036, upon infrequent intra-ocular administrations, induces biological responses consistent with expected moleculat mechanism of action and long-lasting distribution in relevant eye tissues.
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