Published on 08/17/2022 06:00
(Credit: International Center for Eye Health/Disclosure)
Worldwide, 80 million people suffer from glaucoma, a chronic disease that leads to progressive vision loss. Its causes have not been fully elucidated, it is currently being treated with a focus on the only modifiable risk factor, intraocular pressure. However, even the most advanced treatments in this sense are not always able to prevent blindness. Now, a study of a genetic mutation that increases the risk of Alzheimer’s disease, a neurodegenerative disease and a leading cause of dementia, shows that the variant may protect against the eye problem. According to the authors, the results pave the way for a direct fight against the disease, with the possibility of restoring the optic nerve.
The study, published in the journal Immunity, builds on the important 2017 discovery that neurodegenerative diseases, which are characterized by the destruction of central nervous system cells, share the APOE4 variant of the Apolipoprotein E gene. The development of glaucoma, discovered two years ago by a team of scientists from Mass Eye and Ear and Brigham and Women’s Hospital, in the USA, led by Melika Marjeta, professor and glaucoma specialist.
The relationship between the mutation and its protective effect against eye diseases, however, is not yet fully understood. Now, coordinated by Margeta, researchers from the same institutions have discovered how APOE4 can prevent glaucoma. The study, conducted in animal models, showed that gene therapy targeting the variant is able to prevent the destruction of neurons associated with blindness.
“Our research provides a greater understanding of the genetic pathway that leads to permanent blindness in glaucoma and, most importantly, points to a potential treatment to address the root cause of vision loss,” Marjeta said in a note. “This study shows that the disease cascade mediated by the APOE genes is clearly harmful in glaucoma and that when you interfere with it genetically or pharmacologically, you can actually stop the disease.”
In the study, the scientists attempted to induce glaucoma in mice genetically engineered to display the APOE4 variant. Although intraocular pressure was elevated, these animals did not experience damage to the retinal ganglion cells that are damaged by the disease. To understand the process, the researchers performed genetic sequencing to determine which genes were turned on and off in the animals’ brains in a type of immune system cell called microglia, which is linked to glaucoma.
Although the exact cause of the disease is unknown, glaucoma is believed to be caused by a microscopic inflammatory process in the optic nerve. In patients, microglia are always activated. In healthy tissue, this important cell protects the eyes and brain, but in degenerative diseases such as Alzheimer’s and Parkinson’s, it can produce toxic molecules, including a substance called galectin-3, that destroys nerve cells and other cell groups.
In the study, the scientists noted that in animals genetically modified to display the APOE4 variant, elevated intraocular pressure could not cause microglia to go from being healthy to one that might be toxic. Without its activation, he stopped producing galectin-3 and, accordingly, the neurons were protected. The conclusion was that trying to block the synthesis of this molecule could prevent glaucoma. To reinforce the idea, the researchers evaluated samples of human eye tissue and saw that in patients with progressive blindness and the common variant of APOE, this substance was increased. However, in those with the APOE4 mutation, it was almost undetectable.
“This was an impressive discovery and led to the testing of whether a pharmacological intervention could prevent galectin-3, which can treat glaucoma,” says study senior author Oleg Potovsky, associate professor of neurology at Harvard Medical School. The scientists used galectin-3 inhibitors, which can be derived from natural sources and are currently in clinical trials to treat pulmonary fibrosis.
The result was that injections of the galectin-3 inhibitor prevented the disease cascade in mice with glaucoma, and retinal ganglion cells were protected, even with elevated intraocular pressure. “Our findings provide an explanation for why APOE4 is associated with a reduced risk of glaucoma and demonstrate that the APOE signaling pathway is a promising target for neuroprotective therapies for this disease. However, we still do not know why the same allele is harmful in Alzheimer’s disease, but it is protective against neurodegenerative eye disease. ‘ says Butovsky.
“Glaucoma is a very serious disease because the losses are permanent, and the damages cannot be compensated. All the treatment we have today is to reduce the pressure in the eye, but what happens inside the organ is unknown,” Jonathan says. Lake, MD, medical director and ophthalmologist at Grupo Opty. “This study opens the way to addressing the cause of glaucoma, which is a very important step. In the images published in the study, we can see cell growth and regeneration,” he says, noting that it is still preliminary research with animals. The specialist states that since it is a serious disease, it is necessary to monitor it frequently, especially in the case of people with a family history.
According to Melika Marjeta, the team now plans to look in more detail at galectin-3 inhibitors as potential treatments for glaucoma, and run tests in other animal models. In addition, they want to know the least invasive ways to give the substance, either orally or in the form of a slow-release gel. Scientists are already analyzing eye fluid and serum samples from patients undergoing glaucoma surgery to determine the population that would benefit from galectin-3 inhibitors. The results will be the first step toward clinical trials in humans.
Three questions for
Ramon Barreto, ophthalmologist and retinal specialist at Visão de Olhos . Hospital
Previous studies have already suggested associations between the glaucoma and Alzheimer’s gene and the APOE4 gene. What will be the relationship between them?
Overexpression of the protein APOE4, according to some scientific studies, carries a greater risk of Alzheimer’s disease, but it would reduce the risk of glaucoma damage. APOE is known to function in regulating the homeostasis (homeostasis) of microglia, cells that support and protect neurons, in both the retina and the central nervous system. Glaucoma damage and consequent blindness occurs when we have degeneration of the ganglion cells, which are the neurons responsible for transmitting visual impulses from the photoreceptors of the retina to the brain.
Are the mechanisms that lead to glaucoma and vision loss from this cause well understood?
Glaucoma is known to occur due to ganglion cell degeneration. But the exact mechanism that leads to this degeneration has not yet been fully elucidated. The main risk factor for ganglion cell degeneration is increased intraocular pressure. However, there are cases of glaucoma damage even with normal intraocular pressure. One explanation might be specifically the role of APOE in homeostasis in the cells that support and protect these neurons, that is, in glial cells, and especially in microglia.
The study suggests a genetic approach to treating glaucoma. Although still in a preclinical stage, are there expectations that this approach could benefit human patients?
Studies have shown that targeting APOE, as well as galectin-3, would protect retinal ganglion cells, preventing their damage, also called apoptosis, which would prevent visual field loss and blindness. Therefore, the development of drugs and gene therapy for these targets could be of great value in the treatment of glaucoma. Results should always be analyzed with caution, as they are still preliminary studies, tested on animals and it is not yet known whether the response in humans will be similar. Therefore, future studies on this topic are important.
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