Iqbal Ahmad, PhD, professor in the UNMC Department of Ophthalmology and Visual Sciences, and his team have published a new study, identifying a biological mechanism that causes the optic nerve to degenerate independently of eye pressure, that could reshape how the medical community understands and treats normal tension glaucoma.
Glaucoma damages the optic nerve, the cable connecting the eye to the brain. Once that damage occurs, it cannot be reversed. The prevailing theory has been that elevated eye pressure compresses and damages the nerve over time, and most treatments focus on reducing that pressure.
But roughly 30% of glaucoma patients have normal eye pressure, and their optic nerves still degenerate.
It’s a gap that UNMC glaucoma specialists Shane Havens, MD, and Vikas Gulati, MD, both encounter regularly. “I have these perplexing patients where I’ve done everything I can, brought the pressure down as low as I could, and glaucoma is still getting worse,” Dr. Gulati said. Dr. Havens agreed: “Counseling these patients and watching them lose vision despite great pressure control can be disheartening and demoralizing.”
A gene called myocilin is one of the most common genetic factors linked to glaucoma. A specific mutation is associated with glaucoma that develops later in life in patients with near-normal eye pressure.
Dr. Ahmad’s team, led by postdoc research associates Subrata Shil, PhD, and Murali Subramani, PhD, proposed a different culprit: the retinal ganglion cells, whose fibers form the optic nerve itself.
To test this, they took blood from a patient carrying the myocilin mutation and used those cells to create lab-grown human retinal ganglion cells. Using the gene-editing tool CRISPR, they also created an identical set of cells with the mutation corrected for comparison.
Compared to the corrected cells, Dr. Ahmad said, the mutant cells developed poorly, grew shorter nerve fibers, struggled to connect with other neurons and were far more likely to die.
The culprit was a cellular alarm system called the unfolded protein response. The proteins must fold into specific shapes to work properly. In the mutant cells, the myocilin protein was misfolding and piling up inside the cell’s protein-processing center. When too many defective proteins accumulate, the cell triggers an alarm response that is protective in small doses but destructive when it becomes chronic.
“They get stuck, they gunk up the cells, and the cells begin to die,” Dr. Ahmad said.
The team also found that a molecule called REDD1 links this alarm response to another critical system, known as mTOR signaling, that is essential for retinal ganglion cell development and survival. When one system fails, it triggers the other, compounding the damage. When researchers blocked the alarm response with a drug, many problems reversed: cells developed better, nerve fibers grew longer and fewer cells died.
Dr. Ahmad noted that the same protein-misfolding mechanism plays a role in Alzheimer’s, Parkinson’s, ALS and Huntington’s disease, suggesting this research speaks to a much broader challenge in medicine.
The findings are the first demonstration of this mutation’s direct effect on human retinal ganglion cells and could inform treatment for both normal and elevated pressure glaucoma.
“We have a roadmap,” Dr. Ahmad said. “This is the beginning.”