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    Targeting TGF-beta in different ocular diseases

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

     

    In addition, the drug also demonstrated biologic effects in murine models of CNV and GFS. It has a well-documented toxicology profile and favorable therapeutic index, Dr. Janicot noted.

    Evaluating efficacy

    To experimentally evaluate the efficacy of ISTH0036—in close collaboration with the group of Ingeborg Stalmans, MD, PhD (University of Leuven, Belgium)—the drug was administered to C75Bl/6 mice by intracameral or intravitreal injections, and compared with scrambled control oligonucleotide or saline. Injections were performed on day 0 and day 14 after filtration surgery (GFS model) or after laser-induced retina burns (CNV model).

    The investigators evaluated the bleb status in the GFS model every other day until day 28, and the extent of collagen deposition in the bleb area at sacrifice.

    In the CNV model, they evaluated inflammation on day 5 (CD45), angiogenesis on day 14 (FITC-dextran), and collagen deposition on day 28.

    In the GFS model, intracameral administrations—and to a lesser extent, intravitreal injections—of ISTH0036 significantly increased the bleb area compared with the control oligonucleotide- and saline-treated eyes, he noted.

    “ISTH0036 significantly reduced the deposition of extracellular matrix, namely collagen, in the bleb area,” he said. “Analysis of the bleb area showed that ISTH0036 significantly prolonged bleb survival.”

    In the CNV model, intravitreal administrations of ISTH0036 significantly reduced angiogenesis and fibrosis in a sequence-specific manner compared with saline- and control oligonucleotide-treated eyes. On day 5 after the laser application to induce CNV, no difference was observed in the inflammatory process after ISTH0036 was administered compared with the saline or control oligonucleotide.

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