Bi-functional Molecule for Glaucomatous Optic Neuropathy

Project Summary

Nitric oxide (NO) is a key player in relaxing smooth muscle cells and has potential to reduce eye pressure and protect neural cells in glaucoma. However, free radicals generated during the disease process, caused by aging and ultraviolet (UV) light, as well as by high intraocular pressure (IOP), may deplete NO bioavailability.

The cytoprotective and physiological effects of NO (eg, vasodilatation, neurotransmission, and endothelial protection) require extremely small concentrations (pico- to nanomolar), while harmful effects (peroxynitrite radical formation, protein nitrosylation, and apoptosis) take place at higher concentrations of NO, particularly under oxidative stress. The innovative aspects of this proposed research are threefold: i) Creation of a hybrid molecular platform where synergistic actions of both parts produce a physiological level of NO desired for neuroprotection and to lower intraocular pressure (IOP). ii) Delivering exogenous NO, a gaseous molecule to the target tissue is quite a challenge considering its short half-life. Here we have synthesized, characterized a PLGA encapsulated drug nanoparticle with sustained NO release over days. iii) Additionally, we are the first investigator to study the protective effect of a novel dual acting NO-antioxidant hybrid in retinal ganglion cells (RGC) against hypoxic stress. Our preliminary research demonstrated that one such hybrid small molecule, lowers IOP and protects RGCs from oxidative stress induced death. These results are highly encouraging and we will continue further validation studies to understand the synergistic mechanism and action of this bi-functional molecule in both trabecular meshwork and retina. For that purpose, we will use cell culture as well as animal models of ocular hypertension (mimicking open angle glaucoma) and an IOP-independent neuroprotection model (mimicking normal tension glaucoma). 

On successful completion of this project, we will understand the therapeutic dose and efficacy of the lead hybrid compound, for its ability to stimulate cGMP in vitro (trabecular meshwork) and lower IOP in in vivo mouse models of glaucoma. Secondly, we will also gain good insight into the synergistic/additive activity of NO- mediated and antioxidant-mediated neuroprotection of RGC after glaucoma-relevant insults. The results from the proposed work will allow us to seek bigger grant funding from federal government or pharmaceuticals to carry out further translational research studies. Our future goals include lead optimization, formulation development, pharmacokinetic studies via both topical and intravitreal dosing, as well as evaluation of the compounds in different glaucoma models of rodents and higher species to validate the dual activity of IOP lowering and neuroprotection activities. We anticipate that this class of small molecule will be useful as stand-alone or combination therapy for glaucomatous optic neuropathy.