Intracameral drug delivery for therapy of primary open angle glaucoma

• Applicants: Professorin Dr. Miriam Breunig; Professor Dr. Rudolf Fuchshofer
• Subject Area: Pharmacy ; Ophthalmology
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 273871634

Primary open angle glaucoma (POAG) is a neurodegenerative disease of the optic nerve and the second leading cause of blindness. In 2020, more than 76 million people are predicted to be affected worldwide. POAG is often associated with an elevated intraocular pressure (IOP). The IOP is defined by the aqueous humor circulation system. First-line treatment with topical eye drops aims at reducing the eventually increased IOP. Novel strategies for POAG therapy are urgently needed, particularly because hypotensive drugs do not fundamentally treat the root cause of the disease.Decisive events of glaucoma onset and progression are located in the anterior chamber of the eye. Aqueous humor outflow is constricted due to changes of the extracellular matrix of the trabecular meshwork and an enhanced contractility of trabecular meshwork (TM) and Schlemm´s canal (SC) cells. On the molecular level connective tissue growth factor (CTGF) is one of the major mediators of these effects. Based on this knowledge, the goal of the project is to reduce the elevated CTGF expression of TM and SC cells. To this end, we will develop layer-by-layer coated nanoparticles for intracameral injection that will carry either small interfering RNA (siRNA) or micro RNAs (miRNAs). The physico-chemical properties of the nanoparticles will have a strong influence on their efficacy, but also on potential side effects. Thus, based on our recent findings we will coat the nanoparticles with a last layer of hyaluronan for an efficient accumulation in the target tissue. In addition, we will vary the size of the nanoparticles in the range from 50 to 250 nm and test their biocompatibility and functionality in vitro. Thereafter, we will evaluate the layer-by-layer coated nanoparticles (and also model nanoparticles due to lower detection limit) in porcine and human eyes ex vivo and in murine eyes in vivo. It will be of utmost importance to identify formulations that (i) bring a sufficiently high number of nanoparticles to the target tissue for CTGF reduction, that (ii) prevent the clogging of the outflow tissue at the same time, and that (iii) minimize off-target effects in non-target tissues of the anterior eye. In addition, because the nanoparticles may enter the circulation after being eliminated from the eye, we will also evaluate their biodistribution to other organs like the kidney, the liver, the spleen and the heart to minimize potential side effects. Finally, we will investigate promising formulations in a mouse glaucoma model in vivo with respect to their influence on the IOP and the prevention of axon loss in the optic nerve head. We expect that our studies will contribute significantly to developing a causative therapy for POAG.

• DFG Programme: Research Grants