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Of Mice Not Men: New Alzheimer's, nicotine pathways; making blood type O


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Of Mice Not Men: New Alzheimer's, nicotine pathways; making blood type O

This is a recurring column on early stage research in animals or other laboratory models that has not entered the clinic yet but could have implications for future research and development of human medicines.

Liver drug could protect brain cells from Alzheimer's damage

A study out of the U.K.'s Sheffield Institute for Translational Neuroscience has shown that a common liver drug can repair brain cells damaged by Alzheimer's disease, according to a study published in the Journal of Molecular Biology.

Ursodeoxycholic acid, or UDCA, is a substance found in the bile of Chinese black bears and has been used for much of the last century to treat liver disease. Researchers have now found that it also restores activity of a neuron's mitochondria, cell organelles that regulate energy levels. Mitochondria are considered the "batteries" of the cell.

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UDCA works by changing the shape of the mitochondria via redistribution of Dynamin-related protein 1, or Drp-1. Mitochondria are less prevalent in the brain cells of Alzheimer's patients, tend to cluster around the cell's nucleus and are longer. By redistributing Drp-1 on the surface of the mitochondria, UDCA demonstrated an ability to reduce the number of long mitochondria and increase their membrane potential.

Energy changes in brain cells have been found to be one of the earliest signs of Alzheimer's, even before a patient shows symptoms of the disease. Because UDCA is able to reverse mitochondrial dysfunction, it could protect the cells at this early stage, the researchers found.

UDCA demonstrated that it could increase mitochondrial activity in people with sporadic Alzheimer's disease, which is the most common type. Because the drug is already used to treat liver disease, the regulatory pathway is potentially shorter.

Alzheimer's disease is much-researched in the biotech arena and has stumped several big drug developers along the way. Merck & Co. Inc. halted its BACE 1 inhibitor verubecestat's phase 3 trial in February 2018 due to a low benefit-to-risk ratio. The drug aims to reduce amounts of the disease-causing protein amyloid. Similarly, Eli Lilly and Co. and AstraZeneca PLC in June pulled the plug on the BACE 1 inhibitor lanabecestat. Partners Biogen Inc. and Eisai Co. Ltd., meanwhile, have seen some success from early clinical trial data for their drugs aducanumab and elenbecestat.

"Through innovative research we are building a clearer picture of the complexities of the disease and how it develops in the brain," Alzheimer's Research UK Head of Research Sara Imarisio said. "This work suggests a potential new way to target Alzheimer's but needs further exploration before we can know whether this drug used for a liver condition is safe or effective for people with Alzheimer's disease."

Nicotine addiction drug in early research stage

A team of researchers at Washington State University is developing a class of drugs to treat patients with a nicotine addiction by targeting a liver enzyme that metabolizes the chemical, according to a study published in the Journal of Medicinal Chemistry.

By slowing the breakdown of nicotine, levels of the chemical remain higher for a longer time and the person is theoretically less likely to experience a craving. Lower levels of the liver enzyme CYP2A6 have been found to reduce cravings and withdrawal symptoms.

The researchers are testing the ability of several molecules to bind to CYP2A6, inhibiting the enzyme from performing its function. They also need to ensure that those molecules do not have unintended consequences in the body. So far, the researchers have identified 18 potential drugs that could fit the bill.

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Researchers are studying a new way to slow the breakdown of nicotine, potentially delaying cravings and withdrawal symptoms.

Source: Thinkstock

"If you inhibit CYP2A6, it shouldn't bother your overall health," said Philip Lazarus, one of the study's lead researchers. "If we could specifically target this enzyme, people should be fine, and it will possibly help them stop smoking or at least decrease their amount of smoking."

Pfizer Inc. and GlaxoSmithKline PLC both have smoking cessation drugs on the market in Chantix and Zyban, but the drugs have been plagued with side effects that have kept them from becoming blockbusters. Chantix works by facilitating the release of dopamine and serotonin in the same way that nicotine does, but without the harmful chemicals. Zyban was originally prescribed as an antidepressant, decreasing irritability associated with giving up smoking.

Making a universal blood donor

Scientists at the University of British Columbia have developed a method to change any type of blood into type O, often referred to as the universal donor. Because it can be transfused to any patient, blood type O is in high demand around the world, and the ability to synthesize it could save many lives.

Blood type is decided by structures on the surface of red blood cells that comprise different sugars. Type O blood is the simplest and is without the additional sugars on the surface of its cells that define either types A, B or AB blood.

Researchers for decades have theorized that an enzyme could remove those sugars to convert the blood type to the universal donor. But the enzymes needed to do so have been prohibitively inefficient — too many enzymes are required to make the process work.

Researcher Stephen Withers and his UBC team, though, used a method known as directed evolution to genetically engineer a super-powered enzyme that is 170 times more effective at removing the sugar structures on the surface of each blood cell. They published their findings in the Journal of the American Chemical Society.

"I am optimistic that we have a very interesting candidate to adjust donated blood to a common type," Withers said. "Of course, it will have to go through lots of clinical trials to make sure that it doesn't have any adverse consequences, but it is looking very promising."

Before becoming clinically effective, the researchers will have to ensure that the enzymes remove every sugar, as even a small amount is enough to initiate a dangerous immune response that occurs when a person's blood is exposed to that of a different type.

As they move forward, the researchers will continue to genetically engineer their enzyme through directed evolution, making it powerful enough to remove more of the necessary structures.