Gene Therapy Associated With Vision Preservation in Retinal Disease

The manipulation of key enzymes through methods of gene therapy was shown to provide protection against vision loss from multiple retinal conditions.

In trials involving mouse models, gene therapy was shown to aid in the prevention of vision loss or blindness from degenerative retinal injury and retinal disease, according to research conducted by Mount Sinai and published online today in the journal Cell.

These findings could lead to breakthroughs in treatment, such as the development of neuroprotective therapies, for those susceptible to vision loss from retinal degenerative diseases like glaucoma. There is currently no cure for vision loss incurred by this disease.

The study observed interactions between retinal ganglion cells and calcium/calmodulin–dependent protein kinase II (CaMKII), an enzyme. Although the manipulation of CaMKII has previously yielded regulatory changes in key cellular bodily processes and functions, the exact role of CaMKII in retinal ganglion cells is not fully understood.

This study is the first to show that activating the CaMKII pathway helps protect retinal ganglion cells from a variety of injuries and in multiple glaucoma models, the study authors said.

“We uncovered evidence for the first time that CaMKII is a key regulator of the survival of retinal ganglion cells in both normal and diseased retinas and could be a desirable therapeutic target for vision preservation in conditions that damage the axons and somas of retinal ganglion cells,” senior author Bo Chen, PhD, associate professor of ophthalmology and neuroscience, and director of the Ocular Stem Cell Program at the Icahn School of Medicine at Mount Sinai, said in a statement.

In their study, the investigators implemented a gene therapy approach through which they demonstrated how reactivation of CaMKII and its downstream signaling in targeted retinal ganglion cells could provide robust protection against the progression of vision loss or impairment in various disease and injury models.

Injury and disease animal models observed in the study were optic nerve damage, excitotoxicity, a glaucoma model with high intraocular pressure, and a glaucoma model with normal intraocular pressure.

After testing the enzyme across the range of injury and disease animal models, the researchers found that the survival of retinal ganglion cells across many pathologies could be regulated by CaMKII. However, exposure of retinal ganglion cells to toxins or trauma from a crush injury to the optic nerve compromised pathway signaling by CaMKII.

The research suggested a correlation between CaMKII activity and retinal ganglion cell survival, which led the researchers to question whether activating the CaMKII pathway would offer protective qualities to the retinal ganglion cells.

Through methods of gene therapy, they mutated an amino acid within CaMKII to create a more active version of the enzyme, then introduced it into original retinal ganglion cells to boost activity levels. The gene therapy, administered before toxic insult and after optic nerve crush, provided robust protection for retinal ganglion cells.

In the population of gene therapy–treated mice, 77% of retinal ganglion cells survived 12 months after the toxic insult compared with 8% among the population of control mice. The researchers also observed that 6 months after optic nerve crush, survival rates were 77% compared with 7%, respectively.

According to cell activity measured by electroretinogram and patterns of activity in the visual cortex, higher retinal ganglion cell survival rates were associated with greater changes of preserved visual function.

“Our research showed that CaMKII could indeed be a valuable therapeutic target to save retinal ganglion cells and preserve vision in treating potentially blinding diseases like glaucoma," the authors concluded. “The fact that manipulation of CaMKII would involve a one-time transfer of a single gene adds to its vast potential to treat serious retinal conditions in humans. The next step is testing this in larger animal models, which may pave the way for starting clinical trials.” concluded the authors.


Guo X, Zhou J, Starr C, et al. Preservation of vision after CaMKII-mediated protection of retinal ganglion cells. Cell. Puiblished online July 22, 2021. doi:10.1016/j.cell.2021.06.031

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