While studying diabetic retinopathy, a Kellogg researcher made a connection that could one day revolutionize stroke care.
David A. Antonetti, Ph.D., is the Roger W. Kittendorf Research Professor of Ophthalmology and Visual Sciences and a professor of molecular and integrative physiology. His lab studies the protective blood-retinal barrier and how it is compromised in diseases like diabetic retinopathy.
In 2009, the Antonetti lab demonstrated that the bloodretinal barrier is weakened when the protein occludin is compromised. “We began to wonder if something similar might be happening in the other part of the body where blood vessels perform the same protective function—the blood-brain barrier,” says Dr. Antonetti.
To investigate, Dr. Antonetti reached out to blood-brain barrier expert and Michigan Medicine stroke researcher Daniel Lawrence, Ph.D., Frederick G. L. Huetwell Collegiate Professor of Basic Research in Cardiovascular Medicine. Dr. Lawrence was the first to demonstrate that tissue plasminogen activator (tPA), a drug used to restore blood flow in the brain after a stroke, can damage the blood-brain barrier if administered too late after an acute stroke. If given too many hours after a stroke, tPA can trigger a similar—but even more profound— weakening of and damage to blood vessels than what Dr. Antonetti observed in retinopathy models.
Connecting the Dots
At the same time, Dr. Antonetti knew of a drug called ruboxistaurin that was in the development pipeline as a potential treatment for diabetic retinopathy. Clinical trials confirmed its effectiveness in protecting retinal vascular barriers but indicated that when used over many years (as is necessary to manage diabetic retinopathy), its cumulative side effects could be harmful. For that reason, clinical testing for diabetic retinopathy was suspended.
Drs. Antonetti and Lawrence hypothesize that ruboxistaurin could be used with tPA as a one-time rescue treatment for stroke patients—preventing damage to the blood-brain barrier, but without the potential side effects of using tPA too late. This could greatly extend the time for which strokes can be treated. The Antonetti and Lawrence laboratories began the basic science steps necessary to investigate this idea, which has led to exciting new preliminary data and an NIH-funded R01 grant to fully explore the potential of this treatment.
“This is why it’s such an exciting time in medical science,” says Dr. Antonetti. “We’re discovering that important research in one area may actually lead to previously unrecognized therapies for other diseases. Diabetic retinopathy has benefited enormously from cancer research, and we hope that stroke patients can benefit from eye research. Each step forward leads to a new opportunity to share therapeutic advances.”