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Yale Researchers Restore Brain Function Lost from Alzheimer’s Disease

July 16, 2015

Yale Researchers Restore Brain Function Lost from Alzheimer’s Disease

Every 67 seconds another American develops Alzheimer’s disease (AD). So feared by people around the world, only 45% of Alzheimer’s victims are even told they have the dreaded disease.1 The neurodegenerative disorder affects an estimated 35 million people around the globe. Three out of four are women, who slowly lose their cognitive abilities, including their memories, sense of self-identity, and, finally, their lives. It is the only major cause of death that cannot be prevented, slowed, or cured.2 That, however, may be changing.

Repurposing Experimental Drugs

Sometimes, second acts are far better than the first. When AstraZeneca’s experimental cancer drug saracatinib (AZD0530) proved ineffective against metastatic breast cancer in 2011, researchers abandoned their Phase II trials, noting that it was not sufficiently promising to justify continued use.3

Thanks to the National Institute of Health (NIH), its initiative to repurpose experimental drugs led Yale University Medical School researchers to look at AZD0530 from a completely different perspective -- as a possible therapeutic treatment for AD using mice.4

AZD0530 is potent inhibitor of the Src family of tyrosine kinases. Taken orally, these enzymes can penetrate the central nervous system in both mice and humans to modify other proteins in the brain by chemically adding phosphate groups to them (phosphorylation). Phosphorylation usually results in a functional change in the target protein.

In recent years, scientists have developed a much better understanding of how AD actually originates. Some researchers call the complex process the “Toxic Triad.” The triad is composed of a tyrosine kinase called Fyn, which acts as a coupling agent for abnormal Amyloid beta (Aβ) peptides that create plaque in the grey matter of the brain and neurofibrillary tangles made up of Tau proteins. In combination, these proteins are the makings of clinical dementia, known as Alzheimer’s disease.5

A Fast Track to Human Trials

Building on previous studies, Yale scientists focused their research on Fyn kinase and its central role in fostering AD. AZD0530 had already undergone extensive safety tests as an anti-cancer drug in animals and humans and is known to target the same Fyn protein, so Yale researchers were able to bypass that part of the trial process, which could normally take up to a decade.6 Instead, they focused their research on animal studies involving transgenic AD mice. Divided into five test groups, the mice received various amounts of AZD0530, from none at all to 20 mg/kg per day. During the course of their treatment, the mice participated in behavioral testing, known as a Morris water maze and novel object recognition paradigms, in order to study their spatial learning and memory capabilities. Researchers then analyzed the blood and brain tissue of the mice using, among other instruments, a PerkinElmer® VICTOR™ X  Multilabel Plate Reader for all cellular assays in order to determine the interaction between the experimental drug and the Fyn enzyme. PerkinElmer’s high-speed UltraVIEW VoX® 3D spinning disk confocal microscope was also employed for 3D molecular layer imaging of each mouse.7 The UltraView VoX has the ability to image and quantify small synaptic structures in tissue sections as well as evaluate protein levels at these major sites of function. The instrument takes advantage of advances in spinning disk confocal microscopy, and combines information from multiple iterations of a fluorescence intensity/morphological segmentation protocol to construct 3D object masks of an immunologic reaction between AZD0530 and the target proteins.

A New Model In Private -Public Cooperation high speed

Within 18 months, the Yale research team completed its preclinical and clinical safety trials with some remarkable results. After only four weeks of treating the AD mice, AZD0530 restored their memory loss and completely reversed their cognitive impairment with no evidence of chronic toxicity.8

"With this treatment, cells under bombardment by beta amyloid plaques show restored synaptic connections and reduced inflammation, and the animal's memory, which was lost during the course of the disease, comes back," says Stephen M. Strittmatter, the Vincent Coates Professor of Neurology and senior author of the study at Yale.9

Even more remarkable is the speed with which Yale’s research has moved through the successful completion of preclinical and Phase 1b human safety trials. The team is now enrolling 152 participants in a larger, multisite Phase 2a trial to further test the safety and effectiveness of the AZD0530 drug as part of the Alzheimer's Disease Cooperative Study.10

"The 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 [National Center for Advancing Translational Sciences] and AstraZeneca gave us an incredible shortcut in the drug development process," Dr. Strittmatter recently said in an NIH press release.11

"This work demonstrates what can happen when NIH, the biopharmaceutical industry, and academia innovate and collaborate to share resources and knowledge," NCATS Director Christopher P. Austin, M.D. says. "The speed with which this compound moved to human trials validates our New Therapeutic Uses program model and serves NCATS' mission to deliver more treatments to more patients more quickly."12

 

References

1. 2015 Alzheimer’s Disease Facts and Figures, Alzheimer’s Association.

2. Ibid.

3. Phase II trial of saracatinib (AZD0530), an oral SRC-inhibitor for the treatment of patients with hormone receptor-negative metastatic breast cancer, Clinical Breast Cancer, October 2011.

4. In Alzheimer's mice, memory restored with cancer drug, ScienceDaily, March 2015.

5. Fyn Inhibition Rescues Established Memory and Synapse Loss in Alzheimer Mice, American Neurological Association, Annals of Neurology, June 2015.

6. Ongoing Clinical Trial for Anti-Cancer Drug Found to Restore Brain Function in Alzheimer’s Disease Rodent Model, Alzheimer's News Today, April 2015.

7. Ibid.

8. Fyn Inhibition Rescues Established Memory and Synapse Loss in Alzheimer Mice, American Neurological Association, Annals of Neurology, June 2015.

9. Alzheimer’s missing link found: Is a promising target for new drugs, YaleNews, September 2013.

10. Ibid.

11. Repurposed experimental cancer drug restores brain function in mouse models of Alzheimer’s disease, National Institutes of Health, March 2015.

12. Ibid.


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