PKal May Join VEGF as DME pathway

A protein called PKal (plasma kallikrein) and its associated molecules are key players in an inflammatory molecular pathway involved in diabetic macular edema, according to a study published in Diabetes. This finding may eventually lead to new treatments in addition to or instead of anti-vascular endothelial growth factor (VEGF) agents.

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Researchers at the Joslin Diabetes Center, Harvard Medical School, Boston, and the Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, noted that anti-VEGF therapies have greatly improved the treatment options for DME in recent years, but only about one-half of DME patients are fully responsive to these new therapies.

Research in the lab of Edward P. Feener, Ph.D., an investigator in the Section on Vascular Cell Biology and director of the Proteomics Core, Joslin Diabetes Center, and an associate professor of medicine at Harvard Medical School, has shown that a substantial percentage of patients with DME do not have high levels of VEGF in their vitreal fluid, but do have high levels of a PKal.

The scientists then demonstrated in animal models that the PKal molecular pathway can induce retinal edema through mechanisms that are independent of the VEGF pathway.

The discoveries boost the evidence that agents targeting PKal eventually may be useful in treating DME that is not fully responsive to VEGF inhibitors.

 “Although anti-VEGF therapies have proved effective in some people with [DME], additional therapies are needed to complement existing ones and to treat individuals who do not respond to currently available therapies,” said Helen Nickerson, Ph.D., director of Translation Research at the Juvenile Diabetes Research Foundation (JDRF), which helped support Dr. Feener’s research. “Dr. Feener’s work is critical in elucidating one such potential target for a new DME therapy.”

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In the study, the researchers examined samples of vitreous fluid from 61 patients with diabetic retinopathy or a control group with a non-diabetic form of macular damage. They found that that the DME patients fell into two groups: one with high levels of both PKal and VEGF proteins, and the other with high levels of PKal but not VEGF.

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The researchers followed up using proteomics of vitreous samples from patients with DME, and discovered that the proteins that appear in high abundance in DME are associated more with PKal than VEGF.

In animal models, the scientists showed that diabetic rats that received human DME fluid high in PKal-related proteins but low in VEGF developed increased leakage from retinal blood vessels. This leakage could be blocked by an agent targeting the PKal pathway but not by a VEGF inhibitor. Additionally, diabetic mice genetically modified to lack PKal showed far less retinal blood vessel leakage than non-genetically modified mice.

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“Our findings suggest that heterogeneity of protein changes in DME may partly explain the difference in response to anti-VEGF therapy, and that increased PKal may be a therapeutic target for DME that is independent of changes in the VEGF pathway,” Dr. Feener said

Overall, the researchers said their findings bolstered the case that the PKal pathway can be targeted by drugs independently of the VEGF pathway. “If this pathway turns out to be a significant contributor to DME, it potentially opens up another opportunity in the long term to develop an orally available PKal inhibitor to treat this disease,” Dr. Feener said. Although it is very early early in the development of such treatments, “Oral agents that could be used to treat DME would be a great advance,” he added. “We could reduce the dependency on intravitreal injections and perhaps consider treating patients earlier in the progression of the disease.”

In August 2014, KalVista Pharmaceuticals Ltd. launched an early phase clinical trial of a PKal inhibitor to treat DME. Development of this drug was based on earlier work by Dr. Feener’s lab, which showed that activation of PKal can induce retinal edema in experimental models of diabetic retinopathy.

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In addition to JDRF, the research was supported by JDRF, the Massachusetts Lions Eye Research Fund, and the National Institutes of Health.