Gene therapy may preserve vision in retinal disease and serious retinal injury

Gene therapy in mouse models showed promise in preventing vision loss or blindness from serious retinal injury including optic nerve damage, and from retinal disease including diabetic retinopathy and glaucoma, Mount Sinai researchers report. Their study, published in the July 22 online publication of Cell, could transform treatment for those at risk of major vision loss from retinal degenerative diseases, which currently have no cure.

The researchers focused on retinal ganglion cells, which process visual information by sending images to the brain. These cells can degenerate as a result of retinal injury and retinal disease. The team of researchers demonstrated how reactivation of a key enzyme known as CaMKII and its downstream signaling in retinal ganglion cells through a gene therapy approach provided robust protection against further vision loss or impairment in multiple disease and injury models.

"Neuroprotective strategies to save vulnerable retinal ganglion cells are desperately needed for vision preservation," says 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. "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."

Glaucoma is the leading cause of irreversible visual impairment worldwide, affecting 76 million people, some of whom will progress to blindness despite aggressive treatment to reduce the pressure in their eyes. The major barrier to restoring vision loss from glaucoma and other retinal diseases and injuries is that the long nerve fibers known as axons, which 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 to preserve the RGC's axons and somas (the main body of the nerve cell from which axons branch off along the optic nerve to the brain) and thereby prevent further vision loss are urgently needed.

Mount Sinai researchers 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 retinal ganglion cell's somas or optic nerve injury to its axons led to inactivation of CaMKII and its downstream signaling target CREB (or cAMP response element binding protein). "Intriguingly, we found that reactivation of CaMKII and CREB provided robust protection for retinal ganglion cells," notes Dr. Chen, who is also the McGraw Family Vision Researcher at Icahn Mount Sinai, "and that CaMKII-mediated protection slowed down the disease progression in both glaucoma models."

That reactivation was made possible by 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. The modified version of CaMKII, with a mutated amino acid, was transferred to the targeted cells through an adeno-associated viral vector, a Food and Drug Administration-approved gene delivery system common to the growing field of gene therapy.

"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, a 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 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."

Mount Sinai has filed patent applications for this technology through Mount Sinai Innovation Partners (MSIP), the commercialization arm of the health system. MSIP is in active discussions with multiple companies to help advance this treatment to the clinic.

The Mount Sinai Hospital / Mount Sinai School of Medicine