April 04, 2019 8:35 AM

A Potential New Way to Treat Some of the Most Common Blinding Diseases

Inhibition of atypical kinase C may help manage macular edema and vision loss associated with eye diseases

David Antonetti, MD

Many eye diseases, including diabetic retinopathy and macular degeneration, exhibit increased permeability of blood vessels in the retina.

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These leaky vessels in the central part of the eye can lead to abnormal fluid accumulation and vision loss. Eye injections targeting a specific cytokine, vascular endothelial growth factor (VEGF), have transformed care for these diseases; however, not all patients respond well.

Research by University of Michigan Kellogg Eye Center shows that inhibiting a specific molecule, atypical protein kinase C (aPKC), either genetically or pharmacologically, reduces increased vessel permeability and blocks inflammation.

Blocking a PKC may help protect vision in patients with potentially blinding eye diseases.

“Our data reveal aPKC as an interesting target both for vascular permeability and inflammation and developing aPKC inhibitors may provide a new therapeutic option for blinding eye diseases,” says David A. Antonetti, Ph.D., the Roger W. Kittendorf Research Professor of Ophthalmology and Visual Sciences.

“Our research may help patients with diabetic retinopathy, the leading cause of blindness in working age adults in the United States, and may also lead to new treatments for uveitis, a spectrum of diseases that leads to inflammation of the eye, as well as for retinal vein and artery occlusions,” Antonetti says in a Journal announcement.

SEE ALSO: Patient Data Could Help Predict Need for Diabetic Eye Injections

In a recent study in the American Journal of Pathology, he and colleagues explore the protective effect of an experimental small-molecule aPKC inhibitor. The pre-clinical effects are promising.

Blood-retinal barrier

Good vision requires retinal neurons to send signals to the brain, and retinal neurons must be protected and kept in a healthy microenvironment within the eye.

The microenvironment is maintained, in part, by the blood-retinal barrier.

However, injury or chronic disease can weaken the blood-retinal barrier and increase vessel permeability.

Although VEGF and TNF, a protein that causes inflammation, possess distinct signaling mechanisms, both eventually activate a common pathway, aPKC signaling, to change vessel permeability. Further, aPKC promotes inflammation.

Using genetic mouse models, Antonetti and colleagues showed small molecule inhibitors to aPKC reduced vascular permeability and inflammation, according to the Pathology study findings.

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Saving vision

Antonetti, Kellogg’s scientific director, is one of the world’s experts in the blood-retinal barrier that is essential to sight. He has spent two decades studying how this barrier develops and how diseases such as diabetic retinopathy damage it and lead to vision loss.

He is part of a team that is advancing approaches to protect and restore the barrier so that vision can be saved and restored.

The team, along with other University of Michigan colleagues, also is investigating the formation and loss of the blood-brain and blood-retinal barrier in cancer and stroke.

The work may not only benefit the millions of people with diabetes, but has implications for those who might have a stroke and other brain diseases.