Intracameral drug delivery for therapy of primary open angle glaucoma
Ophthalmology
Final Report Abstract
Goal of the project was to develop novel concepts and drug delivery systems to causally treat primary open angle glaucoma (POAG) and to identify possible new molecular targets and pathways for future treatments. First-line treatment is hypotensive drugs that are applied as eye drops. Shortcomings are poor compliance and extremely low bioavailability. In addition, most drugs that are available as eye drops, do not treat the root cause of the disease which originates in the trabecular meshwork (TM) and Schlemm´s canal (SC) in the anterior chamber of the eye. In this project, five different approaches have been pursuit: (i) Connective tissue growth factor (CTGF) plays a major role in POAG development. Thus, a nanoparticular formulation for the delivery of microRNA (miRNA) to reduce elevated levels of CTGF was developed. In a first step, the optimal nanoparticle size was evaluated with model gold particles of 5, 60, 80 and 120 nm. Significantly more particles were detected in the TM than in the cornea, iris, lens, and ciliary body which is highly beneficial as it minimizes the risk of off target effects. Larger nanoparticles exhibited the highest volume-based accumulation rate in the TM, while smaller particles were superior regarding the particle number. In a next step, two different types of nanoparticles preparations (about 230 nm and 95 nm) for miRNA delivery were fabricated, but they unfortunately failed to reduce elevated CTGF levels. (ii) Rho-associated protein kinase (ROCK) inhibitors are a new class of drugs that treat the root cause of POAG. To achieve a higher drug concentration and to allow for reduced application frequency, fasudil-loaded microparticles were developed for intravitreal application. For the first time, it was shown that an intravitreal depot formulation may be used to supply the anterior chamber of the eye with a drug over a n extended time. (iii) The ROCK pathway has been demonstrated to influence the contractility of cells within the outflow pathway. Additionally, it plays a role in various regulatory mechanisms during eye development and in maintaining homeostasis within a healthy eye. The expres sion of CTGF has been demonstrated to induce alterations in the activity of the RhoA/ROCK pathway, thereby modulating the homeostatic balance of BMP and TGF-β signaling pathways, which is shifted in POAG. (iv) Inactivation of the signaling between angiopoietin 1 (Angpt-1) and its receptor Tie2 is associated with POAG. Because for successful receptor activation a clustering of multiple receptors is required, nanoparticles that carry an Angpt-1 mimetic peptide and bind to Tie2 receptors in a multivalent manner, were developed. The beneficial effects in vitro suggest that Angpt-1 mimetic nanoparticles may be a useful to recover loss of SC cell function. (v) Mammalian target of rapamycin (mTOR) is a downstream mediator of TGF -β which plays an important role during POAG. mTOR inhibitors have recently been tested for potential glaucoma treatment but no delivery system is available to make use of them. To meet this challenge, everolimus-loaded lipid nanocapsules (LNCs) for drug delivery to the TM were developed. Their therapeutic effect is currently being tested. In a next step, the feasibility of these approaches as novel therapeutic treatment option has to be demonstrated in vivo.
Publications
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Causative glaucoma treatment: promising targets and delivery systems. Drug Discovery Today, 24(8), 1606-1613.
Mietzner, Raphael & Breunig, Miriam
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European Association for Vision and Eye Research 2019, Nice, France , PLGA microspheres loaded with a ROCK inhibitor as an intravitreally injectable drug delivery system for the management of glaucoma. Poster presentation Raphael Mietzner
Raphael Mietzner
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European Association for Vision and Eye Research 2019, Nice, France. Distribution of nanoparticles in the anterior chamber of porcine eyes. Poster presentation Tobias Sonntag
Tobias Sonntag
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Controlled released society (CRS) German Local Chapter 2020, Munich, Distribution of nanoparticles in the anterior chamber of porcine eyes. Poster presentation Tobias Sonntag
Tobias Sonntag
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Controlled released society (CRS) German Local Chapter 2020, Munich, Glaucoma therapy - innovative therapeutic concepts and application routes . Invited talk Miriam Breunig
Miriam Breunig
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Controlled released society (CRS) German Local Chapter 2020, Munich, ROCK inhibitor loaded PLGA-microspheres as an intravitreally injectable drug delivery system for glaucoma therapy. Poster presentation Raphael Mietzner
Raphael Mietzner
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Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy. Pharmaceutics, 12(8), 706.
Mietzner, Raphael; Kade, Christian; Froemel, Franziska; Pauly, Diana; Stamer, W. Daniel; Ohlmann, Andreas; Wegener, Joachim; Fuchshofer, Rudolf & Breunig, Miriam
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Angiopoietin-1 Mimetic Nanoparticles for Restoring the Function of Endothelial Cells as Potential Therapeutic for Glaucoma. Pharmaceuticals, 15(1), 18.
Mietzner, Raphael; Pawlak, Ramona; Tamm, Ernst R.; Goepferich, Achim; Fuchshofer, Rudolf & Breunig, Miriam
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Controlled released society (CRS) 25th Anniversary of the German Local Chapter and Inauguration of the BNLF Chapter, Aachen, 2021, Nanoparticles for restoring the function of Schlemm’s canal in primary open-angle glaucoma, Talk Raphael Mietzner
Raphael Mietzner
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Distribution of Gold Nanoparticles in the Anterior Chamber of the Eye after Intracameral Injection for Glaucoma Therapy. Pharmaceutics, 13(6), 901.
Sonntag, Tobias; Froemel, Franziska; Stamer, W. Daniel; Ohlmann, Andreas; Fuchshofer, Rudolf & Breunig, Miriam
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ISER/BrightFocus Foundation Glaucoma Symposium2021, Atlanta, Nitric Oxide – a Regulator of Biomechanical Properties and Molecular Pathways in the Outflow Tissues. Poster presentation Ramona Pawlak
Ramona Pawlak
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DPhG Annual Meeting 2022, Marburg, Glaucoma therapy – innovative therapeutic concepts and application routes. Invited talk Miriam Breunig
Miriam Breunig
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Association for Research in Vision and Ophthalmology Annual Meeting 2023, New Orleans, CTGF tip the balance of growth factors towards TGF-β2 in the trabecular meshwork in vivo and in vitro. Invited talk Rudolf Fuchshofer
Rudolf Fuchshofer
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CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma. Frontiers in Molecular Biosciences, 10.
Dillinger, Andrea E.; Kuespert, Sabrina; Seleem, Amin A.; Neuendorf, Jakob; Schneider, Magdalena & Fuchshofer, Rudolf
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Association for Research in Vision and Ophthalmology Annual Meeting 2024, Seattle, Altered collagen levels in the outflow tissue of DCN-/- mice. Poster presentation Rudolf Fuchshofer
Rudolf Fuchshofer
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Association for Research in Vision and Ophthalmology Annual Meeting 2024, Seattle, CCN2/CTGF levels affect neovascularization and capillary growth in oxygen - induced retinopathy. Invited talk Andrea Dillinger
Andrea Dillinger
