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$2 Million from NIH to Test Macular Degeneration Drug at Penn Medicine: John Lambris

March 1, 2011, Volume 57, No. 24


Dr. John Lambris, Dr. Ralph and Sallie Weaver Professor of Research  Medicine in the department of pathology and laboratory medicine at the University of Pennsylvania School of Medicine, has been awarded a $2 million grant from the National Eye Institute to test a new class of drugs called complement inhibitors in a primate model of age-related macular degeneration (AMD).

The complement system is an evolutionarily ancient branch of the immune response. One of its key functions is to mark both bacterial and dying host cells for elimination by the body’s cellular cleanup services; yet dysregulated complement has also been implicated in at least 30 diseases, including stroke, myocardial  infarction, and AMD. Complement inhibitors, discovered in the  Lambris lab, were licensed by Louisville, KY-based Potentia  Pharmaceuticals and are about to enter a Phase II clinical trial for the  same disease (to be conducted by Alcon Inc.).

While the clinical trial will focus on wet AMD—the more serious form of the condition—the animal studies  covered by the grant will primarily focus on the efficacy and prevention mechanisms of newly discovered complement inhibitors in the early- and late-onset forms of dry AMD found in monkeys at the Tsukuba Primate  Research Center at Tsukuba City, Japan and the SICONBREC primate facility in the Philippines, respectively.

The macula lutea is an oval-shaped yellow  spot near the center of the retina and is the site of the progressive destruction of the macula that is the hallmark of AMD. It is only found in  the eyes of humans, primates, and some birds, said Dr. Lambris, so the animal model of macular degeneration, developed by co-investigator Dr. T. Iwata at the National Institute of Sensory Organs in Japan, represents one of the closest disease models for human AMD. It offers a unique opportunity to study the effect of complement activity and inhibition on the development and progression of AMD, the major cause of blindness in  elderly people in the US.

“This is our life’s opportunity to test  complement inhibitors on disease progression in a clinically relevant  animal model of AMD,” added Dr. Lambris. For the last 10 years, researchers have  shown that activation of the complement system has been associated with  AMD. A genome-wide association study in an American population with  dominantly dry-type AMD revealed a strong association with single  nucleotide polymorphisms (SNPs) of complement genes. The lipid-proteins  clumps that make up drusen—small, yellow or white deposits in the retina  of the eye or on the optic nerve head and one of the most common early  signs of AMD—contain a plethora of active complement molecules in both  humans and non-human primates.

These findings, said Dr. Lambris, have led  his lab to consider the possibility of suppressing complement cascade in the subretinal tissue to delay or reverse the onset of AMD. To test this  hypothesis, they are using analogs of an inhibitor called Compstatin in a  non-human primate model with early-onset macular degeneration that develops drusen in less than two years after birth. Their preliminary results showed drusen disappearance six months after injecting Compstatin  into the eye. Despite years of research on the  molecular correlation between complement activation and disease progression in AMD, many aspects are still unresolved.

Dr. Lambris, in collaboration with Dr. Daniel Ricklin, research assistant professor and Dr. Joshua Dunaief, assistant professor of opthalmology, devoted another part of the grant to a  systematic molecular analysis of complement components in patients with AMD. Together, the studies proposed in the awarded grant are designed to shed more light into the etiology of this severe and abundant disease, and may well pave the way to introduce therapeutic options that interfere with  disease progression much earlier than currently available drugs.

Dr. Lambris holds several patents on Compstatin and clinical use of complement inhibitors. He is the founder of Anosos Biotherapeutics, which develops complement therapeutics for various diseases. It was established using Penn’s UPSTART program, aimed at developing Penn intellectual property by helping faculty form new companies based on their inventions and technological innovations.


Almanac - March 1, 2011, Volume 57, No. 24