Researchers identify mechanism that may cause vision loss in glaucoma

Individuals with glaucoma might one day benefit from a study published June 18 in the journal STEM CELLS in which a “disease in a dish” stem cell model was used to examine the mechanism in glaucoma that causes retinal ganglion cells and optic nerve to degenerate, resulting in loss of vision. The study could result in new therapeutic approaches for this leading cause of blindness worldwide.

“This is one more step in finding new methods to help treat glaucoma in people who suffer from this disease,” said Iqbal Ahmad, Ph.D., a professor in the department of ophthalmology and visual sciences at UNMC. He and colleagues Pooja Teotia, Ph.D., and Meng Niu, Ph.D., conducted the study.

Located in the retina, retinal ganglion cells (RGCs) are nerve cells that send images to the brain via the optic nerve and enable a person to see. Glaucoma attacks these cells, which are not replaced once they die. Researchers are trying to understand why and how glaucoma causes RGCs and the optic nerve to degenerate.

Stem cell modeling of the disease may shed light on this. Over the past decade, significant progress has been made using induced pluripotent stem cell (iPSC) technology to mimic glaucoma. This includes the generation of human RGCs from patients’ iPSCs, which led to the development of a disease model for primary open angle glaucoma (POAG) — the most common form of glaucoma — as well as an optic nerve regeneration.

“These models allow us to test whether or not defects seen in glaucoma have their roots in the development of RGCs,” Dr. Ahmad said. “We generate RGCs and their subtypes through normal developmental time and stages against which the developmental aspects of RGC abnormality can be evaluated in controlled conditions.”

Information about different RGC subtypes is not only important from a functional viewpoint, but also for understanding the underlying mechanism of glaucomatous degeneration, given the emerging evidence that the susceptibility and resistance of RGCs are subtype dependent, he said.

To study the developmental onset of the disease and subtype abnormality Dr. Ahmad and his research team examined the molecular makeup of each of the cells generated in the POAG patient and healthy donor iPSCs using a technique called single cell transcriptome analysis. These POAG patients contained a variation in a gene called SIX6, which plays a role in ocular development. Previous studies have identified a significant association between POAG and variation – called the risk allele – in SIX6.

The team observed that the general trajectories of RGC development in their model were similar between SIX6 risk allele and control RGCs.

“However,” Dr. Ahmad said, “we observed that the differentiation of POAG-patient RGCs was stalled at a primitive developmental stage, keeping them immature and deficient in subtype composition, compared to those generated from healthy donor iPSCs.”

Furthermore, Dr. Ahmad said, POAG-patient RGCs, as compared to healthy donor controls, expressed fewer genes that make some RGCs preferentially resistant to degeneration.

“The immature features of POAG-patient RGCs, deficient in genes that make them degeneration resistant, if persisted in adulthood may make them susceptible to degenerative changes that we observe in glaucoma,” he said.