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Kathy Hasenbach, Leonie Herrnberger, Sabrina Kuespert, Rudolf Fuchshofer, Frank Jaschinski, Michel Janicot; Targeting Transforming Growth Factor beta 2 (TGF-β2) Isoform with ISTH0036 - a Potent and Selective Antisense Oligonucleotide - for the Treatment of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3291.
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Transforming growth factor beta (TGF-β) represents a family of cytokines, which function as primary mediators for TGF-β signaling involved in a wide range of biological processes in human diseases, like oncology, fibrosis and ocular diseases. Several different ocular diseases have been associated with TGF-β, including corneal diseases, proliferative vitreoretinopathy, posterior capsule opacification and glaucoma. In patients with primary open-angle glaucoma (POAG) increased levels of TGF-β2 were found in the aqueous humor (AH). In POAG the AH outflow resistance is increased, leading to an elevated intraocular pressure. The changes in the outflow region are accompanied by alteration in the composition and amount of the extracellular matrix (ECM) and by changes in the actin cytoskeleton of the trabecular meshwork. The changes in the outflow region seem to be caused by TGF-β signaling and its downstream mediator connective-tissue growth factor.
We have developed ISTH0036, a 14-mer phosphorothioate Locked Nucleic Acid- (LNA) modified antisense oligonucleotide gapmer targeting TGF-β2. In vitro studies have been conducted to characterize the effect of the ASO treatment in relevant primary cells, such as human trabecular meshwork cells and murine astrocytes. To characterize the potential use of these ASOs in ocular diseases, studies have been performed to evaluate the effect of ISTH0036 in vivo after intravitreal injection in the mice eyes. The anterior eye segment has been dissected, RNA has been isolated and quantitative PCR has been done to measure the target mRNA downregulation compared to housekeeping genes.
Sequence-specific target downregulation and downstream pathway expression have been carefully analyzed and demonstrated in cell based assays. Intravitreal injection of ISTH0036 into the vitreous humor of mice eyes leads to a sequence-specific downregulation of the target mRNA on day 2 and day 5 after injection in the anterior eye segment.
We have clearly demonstrated that ISTH0036 induces sequence-specific target and downstream pathway downregulation in relevant primary cells in vitro and in tissues in vivo, which makes ISTH0036 a powerful candidate for the treatment of ocular diseases.
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