Monday, October 11, 2021
NIH-funded research reveals clinical trial candidate for people at genetic risk.
According to the results published in Nature aging. The research included analyzes showing that those taking bumetanide, a commonly used drug, and powerful diuretic – had a significantly lower prevalence of Alzheimer’s disease than those who did not take the drug. The study, funded by the National Institute on Aging (NIA), part of the National Institutes of Health, is moving toward precision medicine approach for people at higher risk of disease due to their genetic makeup.
The research team analyzed information in FDA-approved drug samples and brain tissue databases, conducted experiments on mice and human cells, and explored human population studies to identify bumetanide as a leading drug candidate that could be reused for treat Alzheimer’s.
“Although more clinical trials and trials are needed, this research underscores the value of big data-based tactics combined with more traditional scientific approaches to identify existing FDA-approved drugs as candidates for reuse of drugs for the treatment of Alzheimer’s disease. Alzheimer’s, ”said the director of the NIA. Richard J. Hodes, physician
Knowing which of the most significant genetic risk factors for late-onset Alzheimer’s is a form of the apolipoprotein E gene called APOE4, the researchers analyzed data from 213 brain tissue samples and identified Alzheimer’s gene expression signatures, levels at which genes are turned on or off, specific for APOE4 carriers. They then compared the specific Alzheimer’s signatures of APOE4 to those of more than 1,300 known FDA-approved drugs. Five drugs emerged with a gene expression signature that the researchers say could help neutralize the disease. The strongest candidate was Bumetanide, which is used to treat fluid retention often caused by medical problems such as heart, kidney, and liver disease.
The researchers validated the data-based findings by testing bumetanide in mouse models of Alzheimer’s and induced pluripotent stem cellshuman-derived neurons. The researchers found that treating mice expressing the human APOE4 gene reduced learning and memory deficits. The neutralizing effects were also confirmed in human cell-based models, leading to the hypothesis that people already taking bumetanide should have lower rates of Alzheimer’s. To test this, the team narrowed the EHR data sets of more than 5 million people to two groups: adults over 65 who took bumetanide and a corresponding group who did not take bumetanide. The analysis showed that those who were at the genetic risk and took bumetanide had a prevalence of Alzheimer’s disease between 35 and 75 percent lower than those who did not take the drug.
“We know that Alzheimer’s disease will likely require specific types of treatments, perhaps multiple therapies, including some that may target an individual’s unique genetic and pathological characteristics, much like the cancer treatments that are available today.” said Jean Yuan., MD, Ph.D., Program Director for Drug Development and Translational Bioinformatics in the NIA Division of Neurosciences. “The data in this document is a good case for conducting a bumetanide trial trial in people at genetic risk.”
The research team was led by scientists from the Gladstone Institutes, San Francisco, the University of California, San Francisco, and the Icahn School of Medicine at Mount Sinai, New York City. This group is one of more than 20 teams supported by the NIA through a Program Encourage the research community to search, through big data approaches, for medicines that can potentially be reused.
The research was supported by NIH grants R01AG057683, R01AG048017, F31AG058439, R01AG061150, F31AG057150, R21TR001743, and K01ES028047.
ISA guides the systematic planning, development, and implementation of research milestones to achieve the goal of effectively treating and preventing Alzheimer’s disease and related dementias. This research is related to Milestone 7.B, “Initiate research programs for translational bioinformatics and network pharmacology to support rational drug repositioning and combination therapy from discovery to clinical development.”
About the National Institute on Aging (NIA): NIA leads the US federal government’s effort to conduct and support research on aging and the health and well-being of older people. Learn more about age-related cognitive change and neurodegenerative diseases through NIA Alzheimer’s Disease and Related Dementia Education and Referral Center (ADEAR) website. Visit the main NIA website for information on a variety of aging-related topics, at English AND Español, AND stay connected.
Information about the National Institutes of Health (NIH):NIH, the nation’s medical research agency, comprises 27 institutes and centers and is a component of the United States Department of Health and Human Services. NIH is the leading federal agency conducting and supporting basic, clinical, and translational medical research and is investigating the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.
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