"This agreement is an example of the kind of strategic partnerships that we like to build with an industrial partner to bring fundamental research forward as a potential new therapy," said Isaac T. Kohlberg, head of Harvard's technology development office. "By combining the licensing rights and the expertise behind the original findings, and partnering with a leading company such as Merck, we can advance this research into clinical development and application much faster than would otherwise be possible."
Under the terms of the agreement, Harvard will receive a $3 million up-front payment, significant milestone fees and downstream royalties on any marketed products that result from this agreement.
"We are delighted to partner with Harvard on the development of this potential breakthrough technology to treat dry AMD," said Dr. Robert Gould, Vice President Worldwide Licensing and External Research at Merck. "Merck has a long history of research and marketing in ophthalmology including the introduction of the first glaucoma therapy in 1958. This agreement demonstrates Merck's continuing commitment to treat major diseases of the eye. Fundamental research at major research universities such as Harvard is having a more immediate impact on therapeutic approaches, and this new dynamic requires both world class science and strong partnerships between technology transfer organizations, academic scientists and industry," Dr. Gould added.
Eight million people in the U.S. have the dry form of AMD, a condition for which neither definitive causes nor cures are known.
Studies on vision and AMD by Dr. Rando have recently culminated in the development of small molecule antagonists of the visual cycle that may protect against dry AMD and Stargardt disease.
Dr. Rando's approach is to prevent toxic substances called lipofuscins from forming in the eye. "Lipofuscin accumulation appears to be a major risk factor for macular degeneration, including the age-related type," said Dr. Rando. Toxic constituents of lipofuscin are generated as byproducts of the visual cycle, a complex chemical pathway that is required for the maintenance of the light gathering components of the eye called retinal photoreceptors. The macula is the portion of the retina that is responsible for color and high acuity vision.
When light hits the retina, which is packed with photoreceptor cells, a complex chemical process occurs that stimulates the optic nerve. During this process, essential components of the photoreceptors, called chromophores, are photochemically modified as a consequence of light absorption. Retinal photoreceptors and associated retinal pigment epithelial cells repair these altered chromophores, but the photochemically modified chromophores can also chemically react with other molecules in the retina, especially lipids, to form toxic by-products. The most common by-products of the vision cycle comprise the lipofuscins, which are very stable toxic substances, and not readily eliminated from the eye.
The lipofuscins can be compared to cholesterol because monitoring and lowering these toxic molecules could do for macular degeneration what cholesterol measurements and cholesterol-lowering drugs, such as the statin class, have done for cardiovascular disease. In some cases of macular degeneration called geographic atrophy, holes appear in the macula that are surrounded by clumps of lipofuscin. "One of the worrisome issues with the lipofuscins is that they are insoluble and form aggregates akin to plaques, suggested Dr. Rando. In addition, he noted the lipofuscins and their readily formed oxidation products are highly retinotoxic for a variety of reasons, which includes their propensity to react with DNA and other macromolecules.
One way to stop the formation of lipofuscin is to put a brake on the vision cycle. In a 2005 issue of Biochemistry, Dr. Rando and his collaborators reported finding key elements in the visual cycle pathway and designed a group of novel small molecule antagonists for some of them. Their approach is illustrated by studies on the functional and mechanistic importance of a protein that is almost exclusively found in the retinal pigment epithelium, and is essential for the vision cycle. In two additional and previous publications in 2004, one in the Proceedings of the National Academy of Sciences and another in Cell, Dr. Rando and his team found evidence to suggest that this protein is involved in the slow step of the cycle, making it a potential drug target. As anticipated, small molecule antagonists of this target both selectively inhibit this protein's function and slow the visual cycle. As further described in the January 24, 2006 issue of the journal Biochemistry, Dr. Rando, members of his research team, and collaborators at Columbia University, selected small molecule antagonists that they had previously synthesized and showed that they can also stop production of the retinotoxic lipofuscins. In mice that are genetically predisposed to forming excessive amounts of lipofuscin, administration of the inhibitors completely blocked formation of the A2E lipofuscins, the most common components of lipofuscin found in the eye.
"Our own work focuses on basic, mechanistic chemical approaches to understanding the biology of vision. Now that it is time to translate this work into the clinic, it is important to hand it over to experts at using applied chemical and biological approaches," Dr. Rando said. "These approaches are far more effectively executed in the pharmaceutical industry than in academia and that is why we are partnering with Merck."
HARVARD MEDICAL SCHOOL
Harvard Medical School has more than 7,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, the CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.