Gene therapy protects optic nerve cells and preserves vision in mouse models of glaucoma

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. “

Bo Chen, Ph.D., principal investigator of the study, associate professor of ophthalmology and neuroscience 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 compared to 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 task in the water, 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 on the shallow side of a cliff. Finally, an impending test determined that the treated mice were more apt to respond defensively (by hiding, freezing, or shaking their tails) when shown an air stimulus designed to simulate a threat, compared to untreated mice.

“If 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,” Chen concluded.