Multimillion-dollar Deal Takes Aim at Macular Degeneration

HMS announced on May 23 that it has signed a multimillion-dollar license agreement with Merck & Co. to develop potential therapies for macular degeneration. The agreement—one of the largest in the School’s history—provides Merck, through an affiliate, with licenses to specific molecules that could slow the generation of toxic byproducts that form in the eye; the substances have been implicated in some forms of age-related macular degeneration (AMD) and Stargardt disease, a juvenile form of blindness. The agreement also establishes a research collaboration between Merck and Robert Rando, the Gustavus Adolphus Pfeiffer professor of biological chemistry and molecular pharmacology at HMS, and provides Merck, through an affiliate, with exclusive rights to Rando’s intellectual property in this area.

Photo by Stephanie Mitchell

Robert Rando

“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 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 $3 million in up-front payments, significant milestone fees, and downstream royalties on any marketed products that result from this work.

“We are delighted to partner with Harvard on the development of this potential breakthrough technology to treat dry AMD,” said Robert Gould, vice president worldwide licensing and external research at Merck. “This agreement demonstrates Merck’s continuing commitment to treat major diseases of the eye.”

Eight million people in the U.S. have the dry form of AMD, a condition for which neither definitive causes nor cures are known.

Basic scientific studies on vision by Rando have recently culminated in the development of small molecule antagonists that can be used to partially block the visual cycle and may protect against dry AMD and Stargardt disease.

Toxic Waste
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 Rando. Toxic constituents of lipofuscin are generated as byproducts of the visual cycle, a complex pathway required for the maintenance of retinal photoreceptors. In AMD, deterioration occurs in the macula, the central portion of the retina, responsible for color and high-acuity vision.

When light is absorbed by the retina, which is packed with photoreceptor cells, the optic nerve becomes stimulated. During this process, components of the photoreceptors, dubbed chromophores, are photochemically modified as a consequence of light absorption. The photoreceptors and associated retinal pigment epithelial cells repair the photochemical products, but they can also chemically react with other molecules in the retina, especially lipids, to form toxic byproducts. This is caused by an inefficiency in the system. The most common byproducts of the vision cycle are the lipofuscins, very stable toxic substances not readily eliminated from the eye.

“One of the worrisome issues with the lipofuscins is that they are insoluble and form intracellular aggregates akin to plaques,” explained Rando. In addition, he noted that lipofuscins and their readily formed oxidation products are highly retinotoxic, having a tendency, for example, to react with DNA and other macromolecules.

‘Braking’ the Disease Cycle
One way to stop the formation of lipofuscin is to put a brake on part of the vision cycle. In a 2005 issue of Biochemistry, Rando and his collaborators reported finding key elements of the visual-cycle pathway and designed a group of novel small-molecule antagonists for a subset of them. In two papers in 2004, one in the Proceedings of the National Academy of Sciences and another in Cell, Rando and his team found evidence that a protein almost exclusively located in the retinal pigment epithelium and essential for the vision cycle 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 impede the visual cycle.

As reported in the Jan. 24, 2006 issue of the journal Biochemistry, 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 these inhibitors completely blocked formation of A2E, the most common component of lipofuscins found in the eye.

“Our own work focuses on basic, mechanistic chemical approaches to understanding the biology of vision,” Rando said. “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. These approaches are far more effectively executed in the pharmaceutical industry than in academia, and that is why we are partnering
with Merck.”

—Tom Fagan

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