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    Targeting TGF-beta in different ocular diseases

    ISTH0036 down-regulates drug signaling in preclinical GFS, CNV models

     

    Take-home message: A potent and selective transforming growth factor (TGF)-β2 LNA-modified antisense oligonucleotide induces biologic responses consistent with the drug’s expected molecular mechanism of action in different preclinical ocular surface disease models.

     

     

    MunichISTH0036—a potent and selective transforming growth factor (TGF)-β2 LNA-modified antisense oligonucleotide (developed by Isarna Therapeutics)—induces biologic responses consistent with the drug’s expected molecular mechanism of action in different preclinical ocular disease models.

    Specifically, biological responses were demonstrated in murine models of glaucoma filtration surgery (GFS) and laser-induced choroidal neovascularization (CNV) following intraocular administration of ISTH0036, said Michel Janicot, PhD, head of preclinical research and development, Isarna Therapeutics.

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    Although it is widely described in the literature that TGF-β is the predominant isoform, the three isoforms of TGF-β and their receptors are present in ocular tissues.

    “The TGF-β family of cytokines is one of the most important ligands involved in modulation of cellular behavior in ocular tissues,” Dr. Janicot said. “TGF-β is involved in epithelial-to-mesenchymal transition and fibrosis, which impair the function of the trabecular meshwork and consequently facilitate increases in IOP.”

    Increased expression of TGF-β can also directly damage the optic nerve and TGF-β signaling is activated rapidly after wounding with 12 hours of an injury. Overactivation of TGF-β2 underlies the pathogenesis of wound healing-related fibrotic diseases in ocular tissues with enhanced extracellular matrix production in most cases, impaired vision and ocular tissue homeostasis,” he explained.

    In preclinical evaluations, ISTH0036 was demonstrated to selectively target TGF-β2 mRNA in a dose-dependent manner. Following a single intravitreal administration, ISTH0036 rapidly cleared from the vitreous humor and was rapidly distributed in the posterior ocular tissues.

    After intravitreal administration, ISTH0036 showed long-lasting tissue distribution and target engagement (downregulation of TGF-β2 mRNA) in relevant target rabbit eye tissues (e.g., choroid/retina, lens, optic nerve).

    NEXT: Evaluating efficacy

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