Potent and selective antisense oligonucleotides targeting the transforming growth factor beta (TGF-β) isoforms in advanced glaucoma: a preclinical evaluation

Kathy Hasenbach, Tine Van Bergen, Evelien Vandewalle, Lies De Groef, Inge Van Hove, Lieve Moons, Ingeborg Stalmans, Petra Fettes, Eugen Leo, Katja Wosikowski, Michel Janicot

Abstract


Purpose: ISARNA Therapeutics is developing highly potent and selective LNA-modified ASO gapmers targeting TGF-β1 and TGF-β2 mRNA. In the field of ophthalmology, glaucoma, the second leading cause for blindness in the US, has been linked to TGF-β activation as a key driver. ISTH0036 is a 14-mer phosphorothioate Locked Nucleic Acid- (LNA) modified antisense oligonucleotide gapmer, targeting the sequence of TGF-β2 mRNA and was developed for therapeutic intervention in ocular diseases. 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 (Isarna proprietary information). The aim of this study was to evaluate the therapeutic potential of ISTH0036 in murine models of glaucoma filtration surgery (GFS) following different intraocular administrations.

Methods: A murine model of glaucoma filtration surgery has been used to evaluate the effect of intraocular ISTH0036 administration on post-operative wound healing. Bleb size and bleb survival were determined after different intraocular administrations of saline, control scrambled oligonucleotide or ISTH0036 (at day of surgery and after two weeks).

Results: Intraocular administrations of ISTH0036 lead to a significant effect on bleb area and survival, as well as decreasing scarring (downregulation of collagen-1 and -3 fibers) in a murine glaucoma filtration surgery model.

Conclusion: Consistent with the expected molecular mechanism of action and demonstrated pharmacokinetic (PK) and pharmacodynamic (PD) properties following intraocular administration, preclinical data with ISTH0036 in murine glaucoma filtration surgery model support the current exploration of the drug candidate in advanced glaucoma patients undergoing trabeculectomy.


Keywords


antisense oligonucleotide, glaucoma, intraocular administration, transforming growth factor beta

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References


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