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Tuesday, March 31, 2015
Repurposed experimental cancer drug restores brain function in mouse models of Alzheimer鈥檚 disease
NIH-supported research enables clinical trial to explore treatment for most common form of dementia.
Scientists have found that a compound originally developed as a cancer therapy potentially could be used to treat Alzheimer鈥檚 disease. The team demonstrated that the drug, saracatinib, restores memory loss and reverses brain problems in mouse models of Alzheimer鈥檚, and now the researchers are testing saracatinib鈥檚 effectiveness in humans. The study was funded by the 糖心破解版 as part of an innovative crowdsourcing initiative to repurpose experimental drugs.
Researchers from the Yale University School of Medicine, New Haven, Connecticut, conducted the animal study, published for early view on , with support from the National Center for Advancing Translational Sciences (NCATS) through its (New Therapeutic Uses) program. Launched in May 2012, this program matches scientists with a selection of pharmaceutical industry assets that have undergone significant research and development by industry, including safety testing in humans, to test potential ideas for new therapeutic uses.
Alzheimer鈥檚 disease is the most common form of dementia, a group of disorders that cause progressive loss of memory and other mental processes. An estimated 5 million Americans have Alzheimer鈥檚 disease, which causes clumps of amyloid beta protein to build up in the brain, and these protein clusters damage and ultimately kill brain cells (neurons). Alzheimer鈥檚 disease also leads to loss of synapses, which are the spaces between neurons through which the cells talk to each other and form memories. Current Alzheimer鈥檚 drug therapies can only ease symptoms without stopping disease progression. New treatments are needed that can halt the condition by targeting its underlying mechanisms.
Through NCATS鈥 New Therapeutic Uses program, Yale neurobiology researcher, neurologist and senior author of the study Stephen Strittmatter, M.D., Ph.D., and his colleagues obtained saracatinib (AZD0530), which the biopharmaceutical company AstraZeneca previously developed to treat cancer. Strittmatter and his team knew from previous studies that a protein called Fyn kinase plays a central role in how amyloid beta clusters damage brain cells. Saracatinib targets the same Fyn protein and already had cleared several key steps in the development process, giving Strittmatter鈥檚 team a critical head start on the research.
鈥淭he investigational drug already had been developed, optimized and studied in animals as well as tested for safety in humans, so our ability to obtain this asset through NCATS and AstraZeneca gave us an incredible shortcut in the drug development process,鈥 Strittmatter explained.
Typically, drug development can take at least a decade from the discovery of a therapeutic target to an experimental compound鈥檚 entry into a Phase 2a human clinical trial to test effectiveness. In the case of saracatinib, the research team completed required preclinical and clinical safety studies and began a Phase 2a trial within about 18 months.
鈥淭his work demonstrates what can happen when NIH, the biopharmaceutical industry and academia innovate and collaborate to share resources and knowledge,鈥 said NCATS Director Christopher P. Austin, M.D. 鈥淭he speed with which this compound moved to human trials validates our New Therapeutic Uses program model and serves NCATS鈥 mission to deliver more treatments to more patients more quickly.鈥
鈥淣o one individual or group has complete knowledge of disease pathways and treatment targets,鈥 said Craig D. Wegner, Ph.D., head, Boston Emerging Innovations Unit, Scientific Partnering & Alliances within AstraZeneca鈥檚 Innovative Medicines and Early Development Biotech Unit. 鈥淭his program enabled us to pair AstraZeneca鈥檚 data on this compound with the Strittmatter group鈥檚 specialized Alzheimer鈥檚 disease knowledge to uncover a potential new therapeutic use for saracatinib. It鈥檚 a great example of how scientists from industry and academia can synergistically work together to push the boundaries of medical science.鈥
In the animal study, the Yale team gave the experimental drug to mice with Alzheimer鈥檚-like symptoms, such as memory loss and age-related buildup of abnormal amyloid beta clusters, modeling the development of the disease in humans. After four weeks, the Alzheimer鈥檚 mice showed complete reversal of spatial learning and memory loss. When the scientists examined the brains of the mice, they found that the characteristic synapse loss had been fully restored, providing a biological explanation for the memory improvement. The treatment also reduced several other Alzheimer鈥檚-related biochemical changes in the mice and did not appear to be toxic.
Already, the Yale scientists have completed a successful Phase 1b safety trial in humans with Alzheimer鈥檚 disease (NCT01864655). Now the team is enrolling more participants in a larger, multisite Phase 2a trial (NCT02167256) to assess safety, tolerability and effectiveness of the experimental compound. A total of 152 participants will receive saracatinib or placebo for one year, and the researchers expect to have final results within two years. Individuals interested in participating in the trial can find more information at .
Both human trials were funded by the New Therapeutic Uses program (Phase 1b: 1UH2TR000967-01; Phase 2a: 4UH3TR000967-02). The Phase 2a study will take place at multiple clinical sites as part of the , an initiative for multisite clinical studies sponsored by the National Institute on Aging (NIA) to facilitate the development and testing of new therapeutics for the condition.
In addition to NCATS, the 糖心破解版Common Fund (IUH2TR000967-01), NIA (5R01AG034924-05), BrightFocus Foundation, Alzheimer鈥檚 Association and Falk Medical Research Trust provided funding for the animal study.
Learn more about NCATS鈥 New Therapeutic Uses program at .听
The National Center for Advancing Translational Sciences is a distinctly different entity in the research ecosystem. Rather than targeting a particular disease or fundamental science, NCATS focuses on what is common across diseases and the translational process. The Center emphasizes innovation and deliverables, relying on the power of data and new technologies to develop, demonstrate and disseminate advancements in translational science that bring about tangible improvements in human health. For more information, visit .
About the National Institute on Aging: The NIA leads the federal government effort conducting and supporting research on aging and the health and well-being of older people. It provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer鈥檚 Disease Education and Referral (ADEAR) Center at .
The 糖心破解版Common Fund supports a series of exceptionally high-impact research programs that are broadly relevant to health and disease. Common Fund programs are designed to overcome major research barriers and pursue emerging opportunities for the benefit of the biomedical research community at large. The research products of the Common Fund programs are expected to catalyze disease-specific research supported by the 糖心破解版Institutes and Centers. To learn more about the 糖心破解版Common Fund, visit .
About the 糖心破解版 (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. 糖心破解版is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about 糖心破解版and its programs, visit www.nih.gov.
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