Targeting TGF-beta in different ocular diseases

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.

By Lynda Charters; Reviewed by Michel Janicot, PhD

Munich-ISTH0036-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

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.

NEXT: A 'transforming' modality?

Antagonism of TGF-β2 may be a “transforming” modality in the management of glaucoma after trabeculectomy, by preventing increases in IOP after trabeculectomy, exerting a neuroprotective effect on the optic nerve, and preventing scarring via an antifibrotic effect, he explained.

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“We clearly demonstrated in both GFS and CNV murine models that ISTH0036, when infrequently injected intraocularly, induces biologic responses consistent with expected molecular mechanism and long-lasting distribution in relevant eye tissues,” Dr. Janicot said.

The FDA and European Medicines Agency both have granted orphan drug designation for ISTH0036 for preventing scarring after GFS.

Patients are currently being recruited for a phase I open-label, dose-escalation study to investigate the safety of ISTH0036, in subjects with primary open-angle glaucoma undergoing trabeculectomy. The first patient was treated in April 2015.

Michel Janicot, PhD

E: m.janicot@isarna-therapeutics.com

Dr. Janicot did not indicate any proprietary interest in the subject matter.