Atypical Protein Kinase C Targeted in Anti-VEGF Unresponsive Patients

David A. Antonetti, PhD

Researchers have identified a new drug target which may help prevent blindness in people with a variety of eye disorders such as diabetic retinopathy (DR) and macular degeneration—especially those that don’t respond to anti-vascular endothelial growth factor (VEGF) therapies.

In several eye disorders that can lead to blindness, increased vascular permeability in the retina seems to play a major role in damaging the eye. Endothelial cells usually help protect the barrier between blood vessels and the neurons on the retina that send messages to the brain. But molecular disruptions can damage the function of these cells, leading to higher vascular permeability and eventually inflammation in the eye, disrupting patient’s vision.

VEGF, the signaling protein, is known to be involved in retinal inflammation, as is Tumor Necrosis Factor (TNF-alpha.) Previously animal studies have suggested that these 2 proteins contribute to different phases of retinal inflammation.

Traditional therapy includes anti-VEGF injections into the eye. This is effective in many patients, but some remain unresponsive. Recent studies have suggested a new target: atypical protein kinase C (aPKC.) The abilities of both VEGF and TNF to increase inflammation require the activation of aPKC.

Lead investigator David A. Antonetti, PhD, professor of Ophthalmology and Visual Sciences at the University of Michigan Kellogg Eye Center, and his team sought to validate aPKC as a drug target for common causes of blindness.

Because aPKC is involved in inflammation caused by both VEGF and TNF, the investigators noted that, “targeting aPKC might provide a superior benefit by targeting a common pathway to vascular permeability, thereby maximizing biological efficacy.”

The team tested the target in multiple ways. First, they looked at mice who’d been genetically engineered to limit the activity of aPKC. When exposed to increasd VEGF and TNFα, the genetically engineered mice seemed to be protected against damage. Next, the team wanted to see if a molecule could have a similar, therapeutic effect. They used a small molecular inhibitor of aPKC in both a genetic mouse model and a separate model of retinal inflammation.

“In both models, the genetic as well as therapeutic intervention reduced the vascular permeability and inflammation,” investigators wrote.

A commentary which accompanied the study suggested that while there are still many unanswered questions about inflammation’s role in blindness, the field is enthused about the prospect of additional studies of aPKC inhibitors.

More preclinical trials, followed by clinical trials, will be necessary before aPKC inhibitors are available for treating patients. However, Antonetti noted in a statement that “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.”

“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,” he added.

The study, "Inhibition of Atypical Protein Kinase C Reduces Inflammation-Induced Retinal Vascular Permeability," was published online in The American Journal of Pathology.