Bill Holton
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Despite advancements in medications and surgical techniques, glaucoma is still the number one preventable cause of irreversible blindness. According to the BrightFocus Foundation more than three million Americans suffer from the disorder. Worldwide, this number approaches 80 million, and it's expected to rise to over 110 million by 2040. There is a range of risk factors for each type of glaucoma.
Unfortunately, studies show that nearly half of those who live with glaucoma aren't even aware they have the disease. And within 15 years of glaucoma diagnosis, 15 percent of patients progress to blindness in at least one eye and 6.4 percent become blind in both eyes.
"Higher than normal eye pressure is often associated with the damage to optic nerve that leads to vision loss, however high intraocular pressure is not the cause of glaucoma; it is merely a risk factor, says Kevin Chan, Assistant Professor of Ophthalmology, Radiology and Neuroscience at NYU Langone Health. "Persons with glaucoma may have normal eye pressure, while others with high eye pressure may be spared altogether."
Is there a deeper, more fundamental cause of glaucoma? That's the question Chan and other researchers are trying to answer with research into three different compounds.
Citicoline
Studies have demonstrated that humans and rodents with glaucoma have lower than normal brain levels of choline. Choline is the building block of membranes that line the nerve cells. It's also a precursor of acetylcholine, which is the chief neurotransmitter for enhancing nerve cell communication, contracting smooth muscles, dilating blood vessels, increasing bodily secretions, and slowing heart rate. "We don't currently know whether these lower choline levels are a causal factor for glaucoma or a secondary effect of the disease," says Chan.
Chan and his team wondered if increasing choline levels might slow or even stop the degradation of the optic nerve and other regions of the brain involved in vision. To answer the question they simulated glaucoma in several dozen rats by injecting transparent hydrogel into the front of the eye to block fluid drainage and increase the pressure. They then administered a three-week course of oral citicoline, a choline-rich compound produced naturally in the brain but also available commercially.
For rats with mildly elevated eye pressure, the optic nerves and other tissues connecting eye and brain continued to deteriorate for up to five weeks after the hydrogel injection. Meanwhile, neural deterioration in the citicoline-treated rodents slowed by over 70 percent. These protective effects lasted up to three weeks after the citicoline treatment was stopped.
"A lot more research, including clinical trials, needs to be done before citicoline supplements can be used to treat glaucoma," advises Chan. "Currently, the only clinical treatment for glaucoma is to reduce pressure either with medications or surgery. Our hope is that this research may lead to a new treatment option for persons with glaucoma—even those without elevated eye pressure. At the very least, perhaps we can delay the onset of age-related glaucoma to a point beyond the average life span."
Protrudin
In the November 2019 issue of AccessWorld we discussed the use of gene therapy to treat a trio of genetic eye diseases: Usher syndrome type 2 (USH2), autosomal dominant retinitis pigmentosa (adRP), and Leber's congenital amaurosis 10 (LCA10). Gene therapy may also be well on its way to enabling new treatments for glaucoma.
"The causes of glaucoma are not completely understood, but there is currently a large focus on identifying new treatments by preventing nerve cells in the retina from dying, as well as trying to repair vision loss through the regeneration of diseased axons in the optic nerve," says Veselina Petrova, Research Fellow with the Department of Neurobiology at Harvard Medical School and Boston Children's Hospital.
Petrova and her team were seeking new methods for treating spinal cord injuries. "Nerve cells in the central nervous system lose the ability to regenerate their axons as they mature, so they have very limited capacity for regrowth. This means that injuries to the brain, spinal cord, retina, and optic nerve have permanent, often life-altering consequences," states Petrova. "Optic nerve and retinal cells are often used to investigate new treatments for stimulating neural regeneration. These cells are accessible, test results are rapid, and new treatments identified in the eye have the potential to be examined for their efficacy in treating other conditions of the central nervous system, such as spinal cord injuries."
The researchers discovered that one of the reasons mature nerve cells cannot self-repair or regenerate is because they have very low amounts of a molecule found in abundance in other, regenerative cells, Protrudin. Protrudin assists in the transport of proteins and growth factors to the tip of growing processes. Nerve cells contain only small amounts of the molecule, but what if they could be encouraged to produce more?
The researchers engineered a virus to inject the gene responsible for Protrudin production into the DNA of cultured mouse brain cells. They then used a laser to injure the cells. They discovered the neurons that were high in Protrudin vastly increased their ability to regenerate.
Next, the team used forceps to crush the optic nerves of mice with artificially enhanced Protrudin levels. "When we measured the amount of regeneration a few weeks after the injury, we found that Protrudin had enabled the axons to regenerate over large distances," says Petrova.
In a different model, the retina was removed from the eye in mice and cultured in a dish. Normally, this insult results in severe retinal cell loss, but when Protrudin production is enhanced, there was a complete protection and no noticeable cell death. This experiment shows that Protrudin could be protective to the injured cells of the eye in conditions such as glaucoma.
The next step? "The use of rodent models of glaucoma, human retina cells and donated retinas to evaluate the safety of this treatment," says Petrova.
Astrocytes
When studying glaucoma it makes sense to focus on the neurons of the retina and optic nerves, the electrically active cells that are damaged by the disease and lead to progressive vision loss. However, there are other cells that may also play an active role, including astrocytes, cells named after the Greek word for "star."
"Astrocytes are star-shaped cells that surround the neurons, much like the packing peanuts in your Amazon box," says Shane Liddelow, Assistant Professor of Neuroscience and Physiology at NYU Langone Health.
According to Liddelow, there are several types of astrocytes that perform various functions. "Some provide nourishment to the neurons, while others remove metabolic waste. During diseases like glaucoma, some others produce toxins that destroy and clear damaged neurons, including retinal and optic nerve cells over-stressed by glaucoma."
Liddelow and his team injected microscopic beads into the eyes of mice in order to block fluid drainage and cause a rise in intraocular pressure. Some of the mice were genetically altered to block the production of the neuron-destroying astrocytes, and these mice suffered significantly less optic nerve damage than the control group. "It's possible for neurons to recover from a certain amount of damage," Liddelow states. "In other instances, the astrocytes will destroy the cell, and then keep going, on and on until eventually the process spirals out of control, leading to the progressive damage associated with glaucoma."
According to Liddelow, this cascading effect may help explain why some people continue to experience progressive vision loss, even after their high intraocular pressure is under control. It may also go a long way toward explaining the mechanisms behind another bewildering eye condition known as sympathetic ophthalmia, a condition where trauma in one eye leads to vision loss in the uninjured eye as well.
Researchers at Vanderbilt University recently discovered that when one eye is stressed, astrocytes in the other eye may actually "bucket-brigade" nourishment up the astrocyte chain into the brain and then down the stressed nerve to help healing. "What if this is a two-way street?" Liddelow suggests. "What if the astrocytes in a severely traumatized eye send neuron-destroying toxins in the opposite direction?"
Liddelow and his team are well on their way to identifying the toxins astrocytes produce to clear damaged nerve cells. "If we can block these toxins, we may be able to limit progressive nerve loss not only from glaucoma, but Alzheimer's and other brain injuries as well."
This article is made possible in part by generous funding from the James H. and Alice Teubert Charitable Trust, Huntington, West Virginia.
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