Thursday July 22, 2021
An NIH-funded research project discovered that the calcium modulator CaMKII protects the optic nerve in mice, opening the door to a new therapy that saves sight.
One form of gene therapy protects optic nerve cells and preserves vision in mouse models of glaucoma, according to research supported by the National Eye Institute at NIH. The results suggest a way forward to develop neuroprotective therapies for glaucoma, a leading cause of visual impairment and blindness. The report was published in Cell.
Glaucoma results from irreversible neurodegeneration of the optic nerve, the bundle of axons in retinal ganglion cells that transmit signals from the eye to the brain to produce vision. Available therapies slow vision loss by lowering high eye pressure, but some glaucomas progress to blindness despite normal eye pressure. Neuroprotective therapies would be a leap forward, meeting the needs of patients who lack treatment options.
“Our study is the first to show that activation of the CaMKII pathway helps protect retinal ganglion cells against various injuries and in several models of glaucoma,” said study principal investigator Bo Chen, Ph .D., Associate professor of ophthalmology and neurosciences. at the Icahn School of Medicine at Mount Sinai in New York.
The CaMKII (calcium / calmodulin dependent protein kinase II) pathway regulates key cellular processes and functions throughout the body, including the retinal ganglion cells in the eye. Yet the precise role of CaMKII in retinal ganglion cell health is not well understood. Inhibition of CaMKII activity, for example, has been shown to be either protective or detrimental to retinal ganglion cells, depending on the conditions.
Using an antibody marker for CaMKII activity, Chen’s team found that CaMKII pathway signaling was compromised whenever retinal ganglion cells were exposed to toxins or trauma due to injury by the retina. crushing of the optic nerve, suggesting a correlation between CaMKII activity and retinal ganglion cell survival.
While looking for ways to intervene, they found that activating the CaMKII pathway with gene therapy protected ganglion cells in the retina. Administering gene therapy to mice just before toxic aggression (which causes rapid damage to cells) and immediately after optic nerve crush (which causes slower damage), increased CaMKII activity and strongly protected the retinal ganglion cells.
Among mice treated with gene therapy, 77% of retinal ganglion cells survived 12 months after toxic aggression, compared to 8% in control mice. Six months after the crushing of the optic nerve, 77% of the retinal ganglion cells had survived against 7% in the controls.
Likewise, increased CaMKII activity via gene therapy has been shown to protect retinal ganglion cells in models of glaucoma based on high eye pressure or genetic deficiencies.
The increased survival rates of retinal ganglion cells resulted in a greater likelihood of preserved visual function, based on cell activity measured by electroretinogram and patterns of activity in the visual cortex.
Three vision-based behavioral tests also confirmed sustained visual function in the treated mice. In a visual aquatic task, the mice were trained to swim to a submerged platform based on visual stimuli on a computer screen. The depth perception was confirmed by a cliff visual test based on the mouse’s innate tendency to walk towards the shallow side of a cliff. Finally, an impending test determined that the treated mice were more apt to react defensively (by hiding, freezing, or shaking their tails) when shown an air stimulus designed to simulate a threat, compared to untreated mice.
âIf we make the retinal ganglion cells more resistant and tolerant to the stresses that cause cell death in glaucoma, they might be able to survive longer and maintain their function,â Chen concluded.
This study was funded by NEI grants R01EY028921, R01 EY024986. NEI is part of the National Institutes of Health.
For more information on glaucoma, visit https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/glaucoma
This press release describes a basic research result. Basic research increases our understanding of human behavior and biology, which is fundamental to advancing new and better ways to prevent, diagnose and treat disease. Science is an unpredictable and gradual process – every breakthrough in research builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without knowledge of basic basic research.
NEI leads federal government research on the visual system and eye disease. NEI supports basic and clinical science programs to develop vision-saving treatments and meet the special needs of people with vision loss. For more information visit https://www.nei.nih.gov.
About the National Institutes of Health (NIH):The NIH, the national agency for medical research, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the principal federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.
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Guo X, Zhou J, Starr C, Mohns EJ, Li Y, Chen E, Yoon Y, Kellner CP, Tanaka K, Wang H, Liu W, LR, Demb JB, Crair MC and Chen B. “Preservation of vision after CaMKII-mediated protection of retinal ganglion cells. Published online July 22, 2021 in Cell. DOI: 10.1016 / j.cell.2021.06.031