Unraveling the Mystery of Normal Tension Glaucoma

Optineurin Plays a Role; Rapamycin a Possible Treatment Approach

This research was supported by BrightFocus

Beatrice Yue, PhD, a 2013-15 BrightFocus grantee, and colleagues have just published the results of their research into optineurin, a protein and gene whose mutations are linked to normal tension glaucoma, a puzzling form of primary open angle glaucoma (POAG). Their results from animal studies also point to an already-approved drug, rapamycin, as a possible way to inhibit or reverse its effects.

Yu is senior author on the report in the open-access journal,  BioMed Central (BMC) Cell Biology (Ying H et al, 2015). She is the Thanis A. Field Professor of Ophthalmology at the University of Illinois at Chicago, College of Medicine, and director of its Ocular Cell Biology Laboratory.

For several years , she and other cell biologists have been studying optineurin’s role, ever since the finding in 2002 that mutant forms of the optineurin gene—whose name is short for “optic neuropathy inducing gene”—are associated with POAG. Optineurin is linked in particular with NTG, an infrequent form of POAG, and with other neurodegenerative disease, including amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease).

NTG is particularly difficult to manage because damage to our vision’s “command central,” the image-preserving retinal ganglion cells (RGCs) of the eye, as well as axons, which are the optic nerve fibers that carry visual signals to the brain, occurs without glaucoma’s classic warning sign of a rise in intraocular pressure (IOP). Clinicians and researchers alike have been searching for an alternative cause for the damage, besides the usual one, physical stress placed on these structures from chronically high IOP.

Dr. Yue has received support from the National Eye Institute for this and other projects; however, BrightFocus is the only nonprofit organization directly funding this important work.

In Vitro Findings Expanded to Rat Model

From in vitro studies (ie, studies of cells that have been isolated from a living organism), Yue and colleagues knew that certain mutations to the gene had the effect of increasing optineurin protein levels in cells. This in turn triggered changes in how optineurin is processed by cells, ultimately leading to RGC death.

The new publication confirms that in animal studies conducted by Yue and her team, the same results were seen in vivo. As an important observation, Yue et al described how optineurin’s destructive impact was seen both in wild-type rats when optineurin was induced, and in rats engineered with optineurin mutations. However, the consequences were more dramatic in the mutant phenotype, compared with optineurin induction. This lends credence to the mutation’s role in causing or contributing to NTG.

These investigators also reported success from intervening in this process with an existing drug, rapamycin, which has been approved by the FDA as a cancer treatment. Rapamycin is known to induce autophagy, a cellular housekeeping function similar to “taking out the trash.” It’s one of the ways cells have of recycling or eliminating unwanted substances.

Autophagy has emerged as a key process that becomes interrupted in cancer and neurodegenerative diseases. And indeed, in their experiments, Yue et al found rapamycin to be effective in reducing over-expressed optineurin and thereby rescuing RGCs from cell death. As they noted in their paper’s Discussion section, “investigators are actively searching for small and safe molecules to enhance autophagy.” Rapamycin already is FDA-approved for renal cancer and is being investigated for other cancers. This early evidence that it, or a compound like it, might interfere with downstream effects of optineurin mutations represents  a significant step towards a potential NTG treatment approach. The finding must be confirmed in further research.

Tracking What Causes a Disease—From Gene Discovery to Mechanism

In recent decades, genes and genetic mutations associated with glaucoma have been discovered through advanced sorting techniques in large, complex studies known as genome-wide association studies. In GWAS, researchers compare the entire set of genes (or “genotype”) of people with glaucoma with those of healthy individuals, to identify and confirm any coding deviations that might be linked to disease.

Unfortunately, the story doesn’t end there. The most common diseases of mind and sight, including the most prevalent forms of glaucoma, macular degeneration, and Alzheimer’s disease, are genetically “heterogeneous,” meaning they are influenced by numerous genetic components. Besides mutations, these genetic determinants may include genes related to an individual’s race, ethnicity, and biological make-up. Disease onset is also influenced by still other factors like age, overall health and resilience, and “environmental” risk factors that affect cell’s functioning, such as diet and exposure to smoking and other toxins, to name a few.

As a result, even after gene discoveries are made, it typically falls to diverse scientists, including cell biologists like Yue and her team, to methodically trace the impact of a genetic mutation on what’s happening at the cellular level. They investigate such things as whether different protein enzymes are produced in greater or lesser quantities as a result of the mutation; the impact of those enzymes on  cellular functions; and the overall consequences over time. This type of close observation is required to come up with a “disease mechanism”—the molecular and biologic explanation for how a disease develops, and the closest thing we have to “proof” of what causes a disease. Generally, cures tend to arise after a disease mechanism becomes documented and accepted, at which time the possible intervention points become clearer.

In this research by Yue et al, there is added value in that their studies have provided early evidence in animal models that an existing FDA-approved drug might intervene in this disease process. As such, they have brought us closer to both understanding and curing NTG, and their insights might also further our understanding of other forms of glaucoma