Novel Gene Therapy Approach Helps Prevent Retinal Vision Loss

Novel Gene Therapy Approach Helps Prevent Retinal Vision Loss

A Mount Sinai researcher has developed a promising gene therapy approach to protecting and revitalizing retinal ganglion cells compromised by severe injury to the optic nerve from diseases like glaucoma.



3 minute read

Over the past decade, Bo Chen, PhD, has increasingly drawn national attention for his breakthrough work in gene therapy to save and even restore the sight of people with degenerative retinal disease. Dr. Chen, Associate Professor of Ophthalmology, and Neuroscience, and Director of the Ocular Stem Cell Program at the Icahn School of Medicine at Mount Sinai, has now taken his lab’s research an intriguing step further with a promising gene therapy approach to protecting and revitalizing retinal ganglion cells compromised by severe injury to the optic nerve from diseases like glaucoma.

In a paper in the journal Cell (August 2021), the investigator reported how the reactivation of a key enzyme known as CaMKII and its downstream signaling in retinal ganglion cells through gene therapy provided robust protection of retinal ganglion cells and preserved vision in multiple diseases and injury mouse models. “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,” says Dr. Chen, who moved his lab three years ago from Yale School of Medicine to Mount Sinai/New York Eye and Ear (NYEE) Eye and Vision Research Institute.

Dr. Chen’s work could prove particularly consequential for glaucoma, the leading cause of irreversible visual impairment worldwide. Glaucoma affects an estimated 76 million people, some of whom will progress to blindness despite aggressive treatment to reduce their intraocular pressure. As Dr. Chen puts it, “The need for neuroprotective strategies to save vulnerable retinal ganglion cells has never been greater.”

As ophthalmologists are well aware, the biggest hurdle to restoring vision loss from glaucoma and other retinal diseases and injuries is the fact that axons—the long nerve fibers that allow retinal ganglion cells to process visual information by converting light that enters the eye into a signal transmitted to the brain—do not regenerate. For that reason, neuroprotective strategies designed to preserve the cell bodies (which contain the DNA of the retinal ganglion cells) and their axons could be critical to preventing further vision loss.

Dr. Chen and his team investigated whether CaMKII could play such a therapeutic role. They tested the enzyme across a wide range of injury and disease animal models, including optic nerve damage, excitotoxicity (where nerve cells are destroyed by the overactivation of glutamate receptors that result in damage to the cell structure), and two glaucoma models that mimicked the pathophysiology of human disease with both high and normal intraocular pressure. The team learned that CaMKII regulated the survival of retinal ganglion cells across many of these pathologies, and that in the small animal excitotoxicity model, insults to the cell bodies or their axons which form the optic nerve led to inactivation of CaMKII and its downstream signaling target CREB (cAMP response element binding protein).

“Intriguingly, we found that reactivation of CaMKII and CREB provided robust protection for retinal ganglion cells,” notes Dr. Chen, “and that CaMKII-mediated protection slowed down the disease progression in both glaucoma models.”

Making that reactivation possible was a gene therapy approach deployed by the researchers to introduce a more active type of CaMKII into the original retinal ganglion cells to boost their activity. This modified version of CaMKII—with a mutated amino acid—was transferred to the targeted cells through an adeno-associated viral vector.

“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,” says Dr. Chen, winner of the Pew Scholars in the Biomedical Sciences Award given to young investigators showing outstanding promise. “The fact that manipulation of CaMKII would involve a one-time transfer of a single gene only adds to its vast potential to treat serious retinal conditions in humans.”