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Center for Translational Research
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Robert Mahley, Karl Weisgraber, Yadong Huang
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In early November of 2006, the Gladstone Center for Translational Research was established to move basic research discoveries into patient therapies. Its first project—a 4-year collaboration with Merck & Co., Inc.—is to pursue therapeutic targets for Alzheimer's, Parkinson's, and other diseases, building upon the promising findings of Gladstone's research on apolipoprotein (apo) E and its isoforms. The Center will be housed in the new Alexandria building right next door to the Gladstone.
“Gladstone's strength has always been in basic research, and we will continue that focus,” said Gladstone president Robert W. Mahley. “But our new Center will bring the benefits of that basic research to patients more quickly. And the research collaboration with Merck is an ideal example of that process.”
The goal of translational research is to accelerate drug discovery by bridging the gap between basic research findings and clinical applications that benefit patients. Gladstone, along with UCSF and many other U.S. academic research facilities, receive federal funding to develop programs to achieve this goal. Larger institutions have a major challenge in coordinating the work of traditionally independent specialties and prioritizing the research for near-term development opportunities.
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Gladstone's approach is different. As a smaller, more focused organization, Gladstone has traditionally collaborated across research teams and institutes. The Center for Translational Research will remain under the nonprofit umbrella. Royalties from any marketed products developed under the agreement with Merck will support additional research.
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The collaboration with Merck will focus on apoE and the extensive basic research done at Gladstone on this protein. ApoE exists in three common isoforms, apoE2, apoE3, and apoE4, which differ from each other by a single amino acid interchange. However, the resulting structural differences give rise to profound differences in the physiological effects of the isoforms. ApoE4 is the greatest known genetic risk factor for AD, while apoE3 and apoE2 are neutral or even protective.
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As part of the agreement, Merck will provide funding for the research programs directed by Dr. Mahley and Gladstone investigators Karl Weisgraber and Yadong Huang. Their findings have identified three potential therapies involving apoE4.
- Small molecules that “correct” the structure of apoE4, blocking its detrimental effects by making it more like apoE3.
- Inhibitors of apoE4-cleaving enzyme. ApoE4 is cut by an enzyme into toxic fragments found in the brains of patients with Alzheimer's disease. Compounds that prevent this cleavage would block the formation of these toxic fragments.
- Inhibitors of apoE4-induced impairment of mitochondrial integrity and function. The toxic fragments of apoE4 impair the action of mitochondria, which provide energy for cells. Drugs that prevent this attack on the mitochondria would prevent the disruption of energy metabolism that leads to the death of neurons.
Under the terms of the agreement between Gladstone and Merck, Gladstone has received an upfront payment for licensing its intellectual property and will receive milestone payments, an annual licensing fee, and downstream royalties for any products developed and marketed that arise from the collaboration under this agreement. In exchange, Merck receives a worldwide, exclusive license to research, develop, and commercialize compounds that are directed to apoE-regulated pathways and result from collaborative research or discoveries under this collaboration by Gladstone.
The collaboration with Merck shows that Gladstone's strategy for high-risk, high-reward research is compatible with more efficient drug development strategies that are emerging in academia and industry.
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As research programs at all three institutes continue to mature, it is likely that many more candidates will be identified for further development in the new Center.
“This agreement is a significant milestone for me personally and for Gladstone in our mission to eradicate major diseases,” Dr. Mahley said. “It is a culmination of more than 25 years of work on apoE and creates the real possibility that therapies will emerge.”
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