Gene therapy protects optic nerve cells and preserves vision in mouse models of glaucoma, according to research published in “Cell.” The findings suggest a way forward for the development of neuroprotective therapies for glaucoma, one of the leading causes of visual impairment and blindness.
Glaucoma is caused by irreversible neurodegeneration of the optic nerve, the ganglion cell axon bundle of the retina that transmits signals from the eye to the brain to produce vision.
Current therapies slow vision loss by reducing elevated pressure in the eye; however, some glaucomas progress blindness despite normal eye pressure.
In this sense, neuroprotective treatments would be a leap forward, satisfying 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 from a variety of lesions and in multiple glaucoma models,” says the study’s principal investigator. Bo Chen, from the Icahn School of Medicine at Mount Sinai in New York (USA).
Route CaMKII (calcium / calmodulin-dependent protein kinase II) regulates processes and functions key cells throughout the body, including the retinal ganglion cells in the eye.
However, the precise role is not well understood of CaMKII in retinal ganglion cell health. Inhibition of CaMKII activity, for example, has been shown to be protective or detrimental to retinal ganglion cells, depending on conditions.
Using an antibody marker of CaMKII activity, the team of Chen found that CaMKII pathway signaling was compromised whenever ganglion cells in the retina were exposed to toxins or trauma from a crush injury to the optic nerve, suggesting a correlation between CaMKII activity and retinal ganglion cell survival.
Looking for ways to intervene, they found that the activation of the CaMKII pathway with gene therapy was protective for the ganglion cells of the retina. Administration of gene therapy to mice just before toxic insult (which initiates rapid cell damage), and just after optic nerve crush (which causes slower damage), increased CaMKII activity and strongly protected ganglion cells of the retina.
Among mice treated with gene therapy, 77% of the ganglion cells of the retina survived 12 months later of toxic insult compared to 8% in control mice. Six months after optic nerve crush, 77% of the retinal ganglion cells had survived versus 7% of controls.
Furthermore, increased CaMKII activity through gene therapy was shown to be protective of retinal ganglion cells in glaucoma models based on elevated ocular pressure or genetic deficiencies.
The increased survival rates of retinal ganglion cells resulted in a greater likelihood of preservation of visual function, according to the cellular activity measured by the electroretinogram and the activity patterns in the visual cortex.
Three tests Vision-based behavioral tests also confirmed sustained visual function among the treated mice. In a visual water task, mice were trained to swim to a submerged platform based on visual stimuli on a computer monitor. Depth perception was confirmed by a visual test based on the mouse’s innate tendency to step onto the shallow side of a cliff.
Finally, another test determined that the treated mice were more likely to respond to the defensive (hiding, freezing or wagging the tail) when they were shown an aerial stimulus designed to simulate a threat, compared to untreated mice.
“If we make the ganglion cells in the retina more resistant and tolerant to the insults that cause cell death in glaucoma, they could survive longer and maintain their function,” Chen concludes.