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Home / Health / A vaccine against Alzheimer's is facing reality

A vaccine against Alzheimer's is facing reality



I In the fall of 2010, Mei Mei Hu, a McKinsey business consultant in New York, received an unexpected invitation from her mother, Chang Yi Wang, and asked her to join her in Shanghai for Christmas.

] Mei Mei has always had a complicated relationship with her mother. "Chang Yi is very special and demanding – which is part of her genius," explains Mei Mei, who sits in a restaurant in Cold Spring Harbor, a former whaling community on the north coast of Long Island. She is tall and slim, with long dark hair pulled back into a recalcitrant ponytail. She was born in 1983 in Great Neck, a suburb of New York. Several years later, her family moved to a large colonial house in Cold Spring Harbor. "I remember coming back from school with a 98 percent test result, and she just said, Kill the last two points next time," she grins angrily. Much to their surprise, I avoided science at school. I spent the rest of my life not working with my parents. Instead, she studied economics at the University of Pennsylvania, where she met her husband, then trained as a lawyer and spent most of her career as a manager counselor.

Chang Yi, on the other hand, is a legend in the field of immunology and biochemistry: She earned her doctorate twice, developed tests for HIV and hepatitis C, and pioneered an HIV vaccine. She is also co-founder of United Biomedical, a prolific drug development company with offices and laboratories in the US, Taiwan and mainland China. Mei Mei had not really talked to her mother about United Biomedical for some time, and she was anxious not to know the company's affairs. "Since I was little, my parents have worked with very little of the boundary between private life and work life," she says. "If you're stressed out at work, you know that, which is one of the reasons why I've always promised never to work with my mother."

However, this Christmas in 201

0, Mei Mei engaged in lengthy conversations with her Mother at the dinner table gradually realized that the company had serious problems legal issues. "I just listened and talked to her and found that there were shareholder disputes and legal action that took up her time and money," she explains. "If they went badly, the company would be in trouble."

Mei Mei began to leaf through the company's documents, and she was surprised by what she found United Biomedical was a company with only a few hundred employees, but it did Health care for animals and humans: production of generic drugs, monoclonal antibodies, blood tests for HIV and Vaccines against foot-and-mouth disease. Chang Yi tried to do everything.

For Mei Mei, it was clear that this wide range of operations was unsustainable. United Biomedical had to be restructured. "Maybe it was my legal background, combined with consulting experience, but sometimes it's just different ways of looking at something. That's why I decided to give it a try, "she shrugs.

She created a large organogram on a whiteboard – separating the Generics, Animal Health, and Monoclonal Antibodies businesses, which are to be hived off into third-party joint ventures. On the chart she made names for each offshoot, just to illustrate: United Biopharma, UBI Asia and United Neuroscience. "I explained to my mother how we reorganize things and just enter wildcard names until we came up with the right names," she recalls. But Chang Yi loved United Neuroscience and "kept saying, after that we could not name it anymore."

A few days before she was due to return to the US, Mei Mei offered to stay six days to resolve legal issues and find joint venture partners. She took a sabbatical from McKinsey and soon realized that her future was in her mother's company. "When you grow up and your parents work their ass off to try to do good and now they may be fooled, you want to defend them. "She shrugs off, partnering with non-core assets, outsourcing some departments and focusing on the part of the business that had the most potential." Chang Yi finds all her products great and they are it also, but it did not take a genius to see that their vaccine business was the most promising. "Mei Mei smiles.

Vaccine research embraced a new field in immunology Endobody vaccines: Most vaccines prepare our body's immune system Fighting against so-called exogenous diseases such as measles or influenza caused by bacteria or viruses entering our blood Endobody vaccines, on the other hand, prepare our immune system to treat malfunctioning of internal body parts that would otherwise ignore it. 19659002] Endobody vaccines are very rare, with only four approved for the market, two for cancer and two for cancer animal health – one of which was developed in 2003 by Chang Yi. This particular drug can completely block the production of testosterone in the body and is currently used as a method of neutering pigs. "It's like a teenager's worst nightmare," Mei Mei says with a dry smile. "Most men find their partner's parents intimidating, and my mother has literally developed a drug that can cause men's testicles to shrink and disappear."

United Biomedical is developing other endobody vaccine candidates This vaccine has been successfully tested on small mammals and monkeys (baboons and macaques) Mei Mei was unfamiliar with the intricacies of biochemistry and decided to seek external opinion and contact prominent vaccine researchers. They were blown away by their mother's work, and one investor suggested they look for other endobody vaccines that worked in the same way Mei Mei could not find any – her mother had created something unique.

After this realization Mei Mei urged her mother to put all her efforts to the Alzheimer vaccine to focus off by the spin-off of United Neuroscience. This was the opportunity of her life, the opportunity to change the lives of millions of people. Chang Yi thought for a few days before agreeing. She asked her daughter to take over the management of the new company. She would return to the lab and finish the work she started, she told her daughter. She wanted to defend herself against Alzheimer's disease.


Chang Yi Wang

Benedict Evans

The Nited Neuroscience laboratory is located on an industrial estate on the edge of Hauppauge, a sprawling city on Long Island. It is a low-rise building divided into small spaces where machines gently shake organic liquids to form peptide chains for vaccines. On a quiet morning in early March, the only sound is the humming of the machines. The Schindlerhaus family is about 20 minutes away by car. There, the team holds meetings and organizes staff parties. Today a management meeting with high-ranking employees takes place in the living room. Other employees are sitting in the kitchen, rooting through a huge Chinese banquet prepared by a chef who keeps putting new dishes on the groan table.

Chang Yi is sitting at the table, occasionally turning the lazy susan to make sure everyone tries each dish as soon as it arrives. Her short, dark hair is neatly cut and combed, she wears a traditional Chinese suit, and she talks fast and talks intensively with storytelling and inspiring researchers.

Chang Yi wanted to become a scientist, she explains as long as she can remember. She was five years old in 1957 and lived in Taipei, the capital of Taiwan, when her mother showed her on the front page of New York a picture of the Chinese-American physicist Chien-Shiung Wu, whom Chang Yi calls "Madame Wu" Mal. Wu had just lifted a basic law of quantum physics called preservation of parity. The physicists at Columbia University, Tsung-Dao Lee and Chen Ning Yang, had suggested that conservation theory was flawed two years earlier, but it was Wu who experimentally confirmed this hypothesis. "Now and then," says Chang Yi, "I decided to become a scientist."

She attended the prestigious Taipei First Girls' High School and studied chemistry at National Taiwan University. In 1973 she became the first Asian woman to be admitted to the graduate program of the prestigious Rockefeller University in New York. This private medical research center is at the center of New York's medical science. Weill Cornell Medicine, New York Presbyterian Hospital and Memorial Sloan Kettering Cancer Center are all located nearby.

At Rockefeller University, Chang Yi studied with four academics she still mentions: Bruce Merrifield, the 1984 Nobel Prize winner for his work on the development of solid-phase peptide synthesis and its potential applications; Henry Kunkel, her dissertation professor and pioneer in clinical immunology; Gerald Edelman, who decoded the structure of antibodies; and Cellular Immunology expert Ralph Steinman, who received a Nobel Prize for the discovery of dendritic cells, a key element in the development of an immune response (the first to be posthumously awarded in 2011).

In 1979, Chang Yi joined Memorial Sloan-Kettering, the world's largest private cancer hospital and research center, as head of the molecular immunology laboratory. She was 27 years old and thus the youngest member of the faculty. There she began to develop clinical applications for her theoretical work. In particular, she was interested in the role of epitope protein fragments of five to six amino acids in length, which play a crucial role in the defense against external bodily diseases.
The human immune system relies on a collection of cells and proteins to identify, neutralize and destroy invaders.

The first two lines of defense of the body are the inflammation and the so-called neutrophilic cells. Inflammation is caused by damaged cells that release chemicals that cause blood vessels to leak into the environment, swell the tissue with fluid, and isolate the foreign substance. Neutrophils are white blood cells that then pick up invaders and break down their protein chains. The next wave of defense – white cells called microphages – "eats" neutrophils, extracts fractions of invading proteins, and binds them to the surface of their cell wall. These fractions are the so-called epitopes.

The presence of foreign epitopes on cell walls of microphages indirectly triggers a type of white cell called a B cell. These are produced in the bone marrow and, when triggered, antibodies that aggregate the invaders and turn them into simple targets for T cells produce a different type of white cell.

After the body has defeated the invasion, it stores a blueprint of successful B cells and T cells. This makes it much faster in fighting another seizure of the same disease to flood the threat before it has time to spread. Most vaccines against diseases imitate an infection by injecting an inactivated or attenuated form of the invader to trigger the immune system. When an infection occurs, the immune system reacts before the person becomes ill.

In 1985, Chang Yi co-founded United Biomedical's Nean Hu, Mei Mei's father. Her work initially involved the detection of epitopes. The body uses epitopes as a shortcut. If you can detect a particular epitope, you know that a particular pathogen exists. Chang Yi hoped to use the same mechanism to develop a quick and easy HIV test. If you could inject harmless synthetic versions of HIV signature epitopes, you could measure the body's immune response to see if it had already hit the virus.

"I was working on the HIV virus in 1985 when a huge dispute broke out between the French Pasteur Institute and the American National Cancer Institute, which had already developed the first test to detect antibodies to the virus back in 1983," she explains you. "They argued about tests for the entire virus. I looked where the antigenic epitopes were. We could synthesize these epitopes and detect HIV antibodies in the blood.

When their HIV and Hepatitis C tests came on the market, large pharmaceutical companies that had been successfully searching for the complete virus for years successfully filed patent infringement claims. The US company Chiron has expelled her Hep-C test from the UK, but in 1996 her claim was rejected in the House of Lords. By then, Chang Yi had shifted her focus to vaccines.

In 1991, she first tried to develop an HIV vaccine. "The problem is that HIV mutates so constantly and so fast," she explains. "We could develop a vaccine for the HIV strain that we had in the lab, but in the field it had already changed and the vaccine could not protect humans."

In 1993, she began working on her first endovaccin – partly because no one else worked in the field, and partly because she thought her work with epitopes was well suited for this type of vaccine. She created synthetic versions of the tiny chains of amino acids that trigger the production of antibodies. In the case of her Alzheimer's vaccine, she was able to develop a mechanism that elicits antibodies to the Alzheimer's protein in the blood. These then attract T cells that attack each protein with a bound antibody.

That should come later. The first endovaccin drug was targeted against prostate cancer and targeted the hormones that produce testosterone as prostate cancer aggressively grows in the presence of testosterone. In order to prove that her idea could work, she began with the castration of pigs.

It took her ten years to develop her first proof of concept – a vaccine that caused the boar's immune system to attack the building blocks of his own testosterone. Without a constant flow of testosterone, the tissues in the penis, scrotum and testicles wither and wither and castrate the animal.

"Drug development is a long and evolving process," explains Mei Mei. "The Immune Castration vaccine began as a human therapeutic, then became a model for testing and creating a library of molecules that could function under different conditions, and was eventually marketed as an animal health application. The entire journey took just over two decades. "

In 2003, after more than ten years, Chang Yi reports that a promising Alzheimer's vaccine developed by the Irish pharmaceutical company Elan failed in clinical trials. Despite some success in the treatment of the disease, side effects included inflammation in the brain. Human trials were initiated after tests on genetically engineered mice removed beta-amyloid clots – one of the key proteins that damage the brain. During the studies, four patients in France developed inflammation in the brain and central nervous system. Further investigations revealed eight more cases.

Chang Yi believed that her new endobody vaccines could solve this problem. "The Elan vaccine stimulated the immune system too much," explains Mei Mei. "Your body has two means to deal with infections – inflammation to catch the intruder and cells that attack and destroy it. The Elan vaccine triggered both reactions. Chang Yi's vaccines use molecules that are so small that they do not cause inflammation. "

Because Chang Yi introduced small chains of amino acids that were synthesized for a specific role in the immune process – essentially only B cells to make antibodies – and because they were bound to a synthetic version of a disease that caused the disease Body already had, they do not trigger inflammation.

Alzheimer's also offered an attractive target for their vaccines because the beta-amyloid protein is very small and very simple epitope that they could mimic. "I could see how easy it would be to make a vaccine better," she recalls. "Alzheimer's is such a low-hanging fruit."


Mei Mei with her mother Chang YiWang at the family home in Cold Spring Harbor, Long Island

Benedict Evans

V Very few people consider Alzheimer's low-hanging Be fruit. The condition was first recorded in 1906 by the German psychiatrist Alois Alzheimer, after he had detected changes in the brain tissue of a deceased in an unusual mental illness patients with symptoms such as memory loss, language problems and unpredictable behavior.

Since then, the disease has become the most common cause of death for women and the second most common cause of death for men in the UK: the fight against Alzheimer's would be a dramatic medical achievement. Half of US deaths in 1900 were due to infectious diseases. By 2010, infectious disease mortality had been virtually eradicated, and the two biggest causes of death were cancer and heart disease. Over the last 15 years, British mortality statistics have shown a steady decline in deaths from heart disease, strokes and most cancers in men and women.

Over the same period, the mortality rate due to dementia was the highest common cause of Alzheimer's disease – has doubled: in part because life expectancy has increased and the effects of the disease are increasing with age. There are currently 850,000 people living with dementia in the UK, and 500,000 – maybe even two-thirds – have Alzheimer's disease. In the UK, the Alzheimer's Society estimates that more than one million people with dementia will be affected by 2025.
There are five remedies available to alleviate the symptoms, but they can not slow or halt the progression of the disease.

Over the past decade, more than 100 drugs for Alzheimer's have been discontinued in development or clinical trials. "We've known Alzheimer's for over 100 years," explains James Pickett, research director of the Alzheimer's Society. "Forty years ago, every form of cancer was incurable – now people are surviving. HIV was almost unknown until 1981, and now it looks like it can be cured. All in all, we have not found anything for Alzheimer's. It is a difficult disease and we are not even sure we fully understand the mechanism. What we do know is that it is a murderer and we have no cure. "Although we do not know much about Alzheimer's, researchers believe that its effects are caused by two rogue proteins, beta-amyloid and tau – high levels of both are found in the brains of people with Alzheimer's."

Beta-amyloid was discovered in 1984 and tau was identified two years later.

Healthy versions of these proteins are important to provide food for the brain cells and to ensure that important chemicals can move freely between them. The blueprint for every protein in your body resides in your DNA, which unwinds so that long chains of amino acids can be arranged in the right order for each protein you need. The initial production is long, straight chains that fold into compact blobs to function properly.

For unclear reasons, damaged beta-amyloid may fold into a "sticky" shape that bulges into a tangle of fibers – called plaques – that accumulate around nerve cells and interfere with cell communication, metabolism, and repair. Tau can also fold into an abnormal shape and clump together with other tau molecules, forming filaments that eventually become entangled within neurons and block the flow of food.

Both proteins can cause brain cell damage, although researchers are not sure if this is the case High levels of beta-amyloid and tau cause Alzheimer's or are symptoms of the disease. Both damaged versions of the proteins can cause neighboring beta-amyloid and tau molecules to also fold – spreading the harmful complications to other cells, disrupting nerve cell connections with other neurons, and slowly starving neurons.

The risk generally increases with age, but a hereditary form of the disease – Alzheimer's disease in its early stages – can affect people over the age of 30 years. Symptoms begin with the difficulty of remembering recent events and developing problems with language, mood, motivation and orientation. Patients become isolated and confused as the disease progresses, which stops bodily functions. Some medications can reduce memory loss and promote concentration, but they only increase the performance of unaffected neurons and do not prevent brain cell killing. There is no known cure. After diagnosis, life expectancy is usually between three and nine years.

Chang Yi's vaccine – UB-311 – couples a synthetic mimic of a common disease with a specific sequence of amino acids that are present only in the damaged beta-amyloid protein and absent in its healthy form. This triggers an antibody response that removes the entangled proteins without causing potentially harmful inflammation.

In January 2019, the company announced the first results of a Phase IIa clinical trial in 42 patients. "We were able to produce some antibodies in all patients, which is unusual for vaccines," explains Chang Yi with a big grin. "We speak of an almost 100 percent response rate, and so far we have seen improvement in three out of three measures of cognitive performance in patients with mild Alzheimer's disease."

Because the Phase II trials are so small, there are yet, there is no statistically valid evidence that UB-311 has an impact on cognitive performance, cognition and memory, but the lack of serious side effects is a big step forward. "They want to see larger numbers, but this seems to be a beneficial treatment." says James Brown, director of the Aston University Research Center for Healthy Aging at Birmingham, "This looks like a silver bullet that can stop or ameliorate symptoms, and if it gets through the next phase, it may be the best chance we have . "


Mei Mei, co-founder of United Neuroscience

Benedict Evans

I In March 2019, the US Defense Company invited Minister of Defense Mei Mei and her husband Lou Reese explain the vaccine at a conference in Telluride, Colorado. United Neuroscience is currently conducting Phase III studies for its Alzheimer's vaccine and has adapted its synthetic peptide technology to develop vaccines for the typical Parkinson's protein. The Parkinson's vaccine known as UB-312 is about to enter Phase I testing. A third vaccine against Tau is in the preclinical phase. Confused tau proteins are not only a hallmark of Alzheimer's disease, but are also found in soldiers and athletes who have recurrent or serious head injuries, which is why the military is interested.

Reese, co-founder of United Neuroscience, was there On the way to the airport, WIRED arrived at the door of the Cold Spring Harbor home. He has ruffled hair and an infectious energy. "If you strive for the concept of democratization of medicine, you need to use new methods to provide patients with troublesome treatments," he argues. "We have one vaccine for Alzheimer's disease, another for Parkinson's and another for migraine, which is being phased out on the basis of Chang Yi's building blocks, and we have a 50-year vision to immunize people with chronic vaccines and chronic aging as productive as vaccines against infectious diseases. "Reese believes that endobody vaccines are the first steps in the democratization of medicine, envisioning a future in which drones will fly directly to patients and give caregivers or family members the opportunity to

He hopes the Ministry of Defense will be interested in new forms of distribution – including a form of high-altitude developed carrier by the German military during World War II, which would use rocket-propelled aircraft as high as possible to the very edge of the atmosphere to fly, so that the earth has turned below them when they come back. You could travel with the vaccine from London to Sydney in about six hours.

After leaving, Mei Mei offers a more solid – and perhaps more realistic – perspective. "What if you went to the doctor and took a reading that could record the protein level in your brain?" She begins. "If it's too high, we'll give you a vaccine and keep toxic proteins in check – you could do it in a kiosk in a mall or on an iPad at home, if it could be monitored by affordable blood tests or retinal scans "We will start working on a migraine vaccine later this year, and the technology can be applied to everything."

Back in the kitchen, Chang Yi drinks tea and avoids discussing Reese's ambitions the goal is simply to use what she has learned in Alzheimer's to treat everything from cancer to HIV. "If we can do that, I would feel that my purpose in life is fulfilled," she nods. My parents gave me the name Chang Yi, which always means happy in English, and if we were to cure Alzheimer's I would be very happy. "

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