A Novel Dual-active Compound to Treat Glaucoma

Suchismita Acharya, PhD
University of North Texas Health Science Center at Fort Worth (Fort Worth, TX)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to June 30, 2020
Disease:
Glaucoma
Award Amount:
$150,000
Grant Reference ID:
G2018056
Award Type:
Standard
Award Region:
US Southwestern
Suchismita Acharya, PhD

Bi-functional Molecule for Glaucomatous Optic Neuropathy

Summary

Glaucoma is a blinding disease and it is estimated that over 76 million people will be affected by this disease by 2020. It is associated with elevated eye pressure and progressive death of retinal ganglion cells (RGCs), as well as degeneration of the optic nerve head (which connects the brain to the eye). Nitric oxide (NO), a small gaseous molecule, is known to act as antioxidant, and is a key player in relaxing the smooth muscle cells and protecting damaged blood vessels.  NO has the potential to reduce eye pressure, with high possibility of protecting the neural cells; however, free radicals generated during optic neuropathy may deplete nitric oxide bioavailability. Our group is working on discovering multi-functional small molecules that may be used for glaucoma treatment to decrease eye pressure and protect neurons, retinal ganglion cells from death.

Details

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 c-GMP 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. 

About the Researcher

I have been working in the field of glaucoma research, on drug design, synthesis and optimization to find a lead drug candidate for clinical research, for the past 17 years. I am an organic and medicinal chemist who is highly experienced in designing and optimizing lead molecules for neuroscience and ophthalmology drug discovery programs at Alcon labs and Novartis. My research included optimizing the physical property of the small molecule using synthetic organic and organo-metallic chemistry, and structure activity relationship study (traditional and structure-based) for topical ocular and intravitreal, intraperitoneal, as well as oral drug delivery. I have also extensive experience in drug permeability, pharmacokinetics, and bioanalytical studies to screen drug compounds in in vitro and ex-vivo models. Our current research is focused on expanding the chemical toolbox for neural signaling and anti-inflammation/anti-oxidant pathways to understand the mechanism of action of the disease pathology associated with glaucomatous optic neuropathy, Alzheimer disease, ischemic stroke as well as angiogenesis. Our lab integrates medicinal chemistry, chemical biology, bio-engineering, and drug delivery, using nanotechnology. We employ synthetic organic and organometallic chemistry to generate a small molecule library for low throughput as well as high throughput screening (target-based as well as phenotypic). The ultimate goal of my lab is to produce novel therapeutic molecules which can progress to human clinical trials for these diseases.

Personal Story

My extensive training as a medicinal chemist and prolonged exposure in ophthalmic drug discovery research in the pharmaceutical industry expanded my horizon to become a drug development scientist specifically focusing on neuroscience. Indeed, one important motivation for me is to facilitate the translation of laboratory findings to patient care. On successful completion of this proposed research, we will be able to identify the efficacy and dose of this novel dual-acting molecule which can be developed as a therapeutic to treat glaucoma.

I am extremely grateful to the donors of the BrightFocus Foundation for this opportunity to advance our own investigations, as well as contribute to the advancement of glaucoma research and clinical care more broadly. These are extraordinary times, with the pace of discovery and development of new therapies occurring so rapidly, yet budgets at Federal institutions supporting biomedical research (such as the NIH) are becoming ever more constrained. Without support from BrightFocus, there’s a risk our own investigations would be paused, indefinitely, at what we believe to be a most critical point.

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