Recent developments in Denali: new antibodies reduce amyloid plaques
April 03, 2018 Source: WuXi PharmaTech
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];Alzheimer's disease (AD) is a neurodegenerative disease common in the elderly, which causes progressive damage to nerve cells in the brain, resulting in cognitive decline and other brain function decline. Patients first have memory defects, and as the symptoms worsen, they gradually lose their ability to take care of themselves. According to statistics, there are approximately 25 million AD patients worldwide. Plaques caused by the accumulation of β-amyloid (Aβ) in the brain are typical of AD patients, which is why many drugs and therapies are intended to target Aβ, but so far, they have not been in clinical phase 3 trials. A successful therapy.
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Recently, researchers at the Washington University School of Medicine have found an effective way to clear amyloid plaques: targeting apolipoprotein E (APOE) genes with antibodies, known. Variants of the gene increase the risk of AD. Although the main component of plaque formation in AD is Aβ, there are also a small number of proteins encoded by the APOE gene. The researchers found that targeting the APOE gene cleared large numbers of plaques in the AD mouse model. Related papers were published in the Journal of Clinical Investigation.
APOE is a gene that provides prognosis in patients with AD. In the brain, APOE helps transport cholesterol to neurons to support their normal function. The APOE gene has three alleles called ε2, ε3 and ε4. Previous studies have found that the ε4 allele is associated with high risk and early onset of AD. It is estimated that up to 65% of AD patients in the US carry an APOE ε4 allele, while 10-15% of AD patients (about 560,000 in the US) have a genotype of APOE ε4 homozygote. APOE ε4 homozygous carriers exhibited faster rates of cognitive decline at multiple stages of the disease, and they also exhibited higher and faster amyloid accumulation.
In this new study, the researchers tested several antibodies targeting the APOE protein using mice with the human APOE gene. They developed these antibodies along with Denali Therapeutics, based in South San Francisco, California. Within six weeks, the researchers injected mice weekly with antibodies or placebo and continued to measure their brain plaques. The results showed that an antibody called HAE-4 reduced the plaque load in the brain of experimental mice by half. More importantly, this antibody only affects APOE protein levels in the brain without affecting APOE in the bloodstream. This is important because normal APOE proteins help the body manage fat and cholesterol, and eliminating it outside the brain can create unwanted off-target effects.
"It turns out that APOE in brain plaques has a different structure than APOE in the blood," said Dr. David Holtzman, director of the Department of Neurology at the University of Washington. "HAE-4 antibodies specifically recognize APOE proteins attached to plaques in the brain. form."
Previous anti-Aβ antibody development results are not satisfactory, and they may cause brain inflammation. However, anti-APOE antibody results may differ: According to Dr. Holtzman, anti-APOE antibodies may have fewer side effects because the APOE protein content in amyloid plaques is very low and the drugs do not bind too tightly. “This means we may find lower levels of immune activation and will not see unwelcome side effects,†commented Dr. Holtzman. The next step for the research team is to test similar antibodies and design further tests to determine if they are safe for humans.
We congratulate the researchers on the results and wish that this discovery will be applied to the clinic as soon as possible, bringing improvements to the condition of AD patients.
Reference materials:
[1] Denali-WashU team clears Alzheimer's plaques in mice by targeting a faulty APOE gene
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