Compstatin – new drug for vision loss, macular degeneration

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University of Florida UF scientists are testing the safety of experimental drug Compstatin for vision loss in macular degeneration patients. In a first-of-its-kind safety research study, University of Florida researchers have injected an anti-inflammatory compound into the eye of a person with a sight-robbing disease.

The procedure was performed last month to test the safety and effectiveness of a synthetic peptide – a small protein fragment – in procedures involving the human eye.

“All patients with macular degeneration have good peripheral, or side, vision, but it’s their central vision that’s affected in both the dry and the wet forms of the disease,” said Dr. Shalesh Kaushal, an assistant professor of ophthalmology and director of the vitreoretinal service in the UF department of ophthalmology.

Macular degeneration affects about 9 million Americans, according to the National Eye Institute. About 15 percent of those people have the wet form of the disease, in which leaky blood vessels crop up like weeds beneath the macula, a part of the retina responsible for central vision.

Doctors can inject the eyes with drugs to stem the abnormal growth of blood vessels, but that approach benefits only the 15 percent of patients afflicted with the wet version, leaving the vast majority of people with macular degeneration in the dark.

These therapies only manage the symptoms, according to Dr. Cedric Francois, the president and CEO of Potentia Pharmaceuticals Inc., the company that designed the anti-inflammatory compound and is funding the safety trial at UF.

“In about 15 percent of people with macular degeneration, you get bleeding in the back of the eye. The drugs that are on the market can stop that bleeding from occurring but they don’t treat the cause of the disease,” said Francois. “The problem was that until recently, no one knew how the illness worked.”

That changed two years ago, when a series of reports in the journal Science shed light on the underlying mechanisms of macular degeneration. The reports revealed a link between the chronic inflammation and tissue damage that accompany both forms of the disease and a genetic defect in the complement system, a series of enzymes that defend the body against pathogens by stimulating a potent inflammatory response.

“Complement is a set of proteins that are often triggered in inflammatory diseases, including the eye in particular,” Kaushal said. “There are now multiple reports that these complement proteins may be overstimulated in wet macular degeneration.”

Those reports allowed scientists to begin tackling the disease from the roots up.

“What’s become clear in the biology of this disease is that there are multiple facets to the disease process. The inflammatory component may be central to the development of age-related macular degeneration because it affects the survival of visual cells and also promotes new blood vessel growth,” Kaushal said.

With that in mind, researchers from Potentia Pharmaceuticals set out to develop an existing family of complement inhibitors called Compstatin for use in the human eye. In animal studies, complement inhibitors have been shown to prevent the inappropriate inflammatory response that accompanies both the wet and dry forms of macular degeneration.

Compstatin and its derivative, POT-4, are the first molecules of their kind to prevent overactivation of the complement pathway.

“Compstatin is a unique complement inhibitor,” said John Lambris, the University of Pennsylvania professor of pathology and laboratory medicine who initially discovered the peptide over 12 years ago. “POT-4 is a much more active version of the original compound.”

Now, teams from Florida, New Hampshire, Minnesota and Arizona are evaluating the safety of POT-4 in humans with the wet form of macular degeneration. The first and third subjects received injections of the peptide at UF in November and December. The second subject was treated in New Hampshire in November.

The UF scientists continue to monitor the subjects closely to gather important information about the safety profile of POT-4. After a safety committee reviews data from the first round of participants, an additional 12 subjects will participate in the study.

“Any peptide or protein that you inject into the eye has the potential for kicking up inflammation,” Kaushal said, noting that because POT-4 is injected locally into the eye in the same method used to deliver existing treatments for macular degeneration, the possibilities for widespread side effects are limited.

Scientists are beginning to explore the role of complement in rheumatoid arthritis, psoriasis, asthma and Alzheimer’s disease.

“There are many human diseases related to complement,” Kaushal said. “That whole area of research has just blossomed over the last four or five years.”

Source: University of Florida, USA

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