Treatment with both drugs improved RGC soma and optic nerve axon survival (right-sided images) compared to untreated eyes (left-sided images).
By Kristen Mulvihill
Scheie Vision Annual Report 2020
Recent studies led by Qi N. Cui, MD, PhD and Joshua Dunaief, MD, PhD discovered two drugs can protect retinal ganglion cells (RGCs) in a mouse model of glaucoma.
Glaucoma is an eye disease that slowly damages the optic nerve and RGCs. It is the leading cause of irreversible blindness worldwide, predominantly affecting individuals over the age of 60. By 2040, approximately 112 million people around the globe are predicted to be living with glaucoma.
This neurodegenerative disease can cause permanent loss of the visual field, usually due to high pressure inside the eye, or intraocular pressure (IOP). There are limited therapeutic mechanisms to effectively slow disease progression; all available treatments reduce IOP. However, glaucoma can continue to progress even in patients who achieve normal IOP levels after treatment, so it is necessary to investigate novel glaucoma therapies.
“All available treatments for glaucoma target IOP control, which is not sufficient to prevent vision loss in a significant number of patients,” explained Dr. Cui.
The teams of Dr. Cui, Assistant Professor of Ophthalmology, and Dr. Dunaief, Adele Niessen Professor of Ophthalmology, sought to examine new treatments with the potential to target other risk factors in glaucoma. They found that the drug deferiprone (DFP) and the compound NLY01 can protect RGCs in a mouse model of glaucoma.
DFP is an orally-administered iron chelator approved by the FDA to treat patients with iron overload. The drug has been used to treat mouse models of macular degeneration and retinal degeneration, both of which are associated with oxidative stress. Oxidative stress, often produced by excess iron, likely plays a role in the development of glaucoma.
To test whether DFP could be protective in glaucoma, the team used microbead injections to induce elevated IOP in a group of mice. The researchers found that administering DFP was protective against RGC and optic nerve loss. These results, published in Experimental Eye Research, suggest that iron chelation by DFP may provide neuroprotection in glaucoma. An additional study showed that DFP was protective in a mouse model of chronic, inherited glaucoma—the DBA/2J mouse. This study was led by Modupe (Funmi) Adetunji, a fourth-year medical student at the Perelman School of Medicine (PSOM).
“DFP or another iron chelator could potentially become a treatment for glaucoma patients after clinical trials are conducted,” said Dr. Dunaief.
In a similar study, the research team investigated the effects of NLY01 in a mouse model of glaucoma. NLY01 belongs to a class of drugs called Glucagon-like peptide-1 receptor (GLP-1R) agonists, which are commonly used to treat Type 2 diabetes. In experimental animal models, other GLP-1R agonists have shown potential in preventing degeneration in Parkinson’s and Alzheimer’s diseases.
To examine the effects of NLY01 on glaucoma, the team, led by PSOM MD/PhD student Jacob Sterling, again used microbead injections to elevate IOP in a group of mice. In this study, IOP elevation triggered the production of cytokines, which are produced by immune cells and can contribute to inflammation. Furthermore, they revealed that cytokines can stimulate transformation of retinal support cells called astrocytes. This transformation can cause these cells to become harmful and promote RGC and vision loss in glaucoma.
The team found that NLY01 successfully reduces retinal inflammation and prevents astrocyte transformation and RGC death in this mouse model of glaucoma. These results, published in Cell Reports, suggest that NLY01 has the potential for clinical use in the treatment of glaucoma. Clinical trials are in progress to test NLY01 in Parkinson’s disease, which will help determine the safety and efficacy of the drug for future glaucoma clinical trials. Neuraly, Inc., a biotechnology company pioneering therapeutics for neurodegenerative diseases, recently announced a strategic sponsored research agreement with UPenn to study the use of NLY01 to target a mechanism of glaucoma.
Given both significant findings, DFP and NLY01 will be tested in additional mouse glaucoma models. If proven protective, Drs. Dunaief and Cui plan to advance the drugs to clinical trials.