SOME people collect stamps, others
vintage cars. As a young PhD student at the University of Cambridge in
the 1980s, Claude Wischik was on a mission to collect brains.
It wasn't easy. At the time, few organ banks kept entire brains.
But Wischik, an Australian who was in his early 30s at the time, was
trying to answer a riddle still puzzling the scientific community: what
causes Alzheimer's disease?
To do that, he needed to examine brain tissue from Alzheimer's patients soon after death. That meant getting families' approval and enlisting mortuary technicians to extract the brains, he says, "no matter the time of day or night". And it wasn't just a few brains: he collected more than 300 across about a dozen years.
In his lifelong investigation, Wischik has backed a minority scientific view
that a protein called tau - which forms twisted fibres known as tangles inside the brain cells of Alzheimer's patients - is largely responsible for driving the disease.
For 20 years much of the scientific community, with billions of dollars of pharmaceutical investment, has supported a different theory that places chief blame on a different protein, beta amyloid, which forms sticky plaques in the brains of sufferers.
But a string of experimental drugs designed to attack beta amyloid has failed recently in clinical trials, and after years on the sidelines Wischik sees this as tau's big moment.
In the early 90s he and his colleagues compared the brains of Alzheimer's sufferers with those of people who died without dementia, to see how their levels of amyloid and tau differed.
They found healthy and Alzheimer's brains could be filled with amyloid plaque but only Alzheimer's brains contained aggregated tau.
What's more, as the levels of aggregated tau in a brain increased, so did the severity of dementia.
"We decided that amyloid isn't what is making people demented," Wischik says.
In the mid-90s he discovered that a drug sometimes used to treat psychosis dissolved tangles in a test tube.
He tried to set up a company to develop the drug as a treatment for Alzheimer's but found American and British venture capitalists wanted to invest in amyloid projects, not tau.
By 2002 he had scraped together $5 million from Asian investors with the help of a Singapore physician who was the father of a classmate of Wischik's son at Cambridge.
The company Wischik co-founded 10 years ago, TauRx Pharmaceuticals, is based in Singapore but conducts most of its research in Scotland, where he now lives. As his tau effort was launched, early tests of drugs designed to attack amyloid plaques were disappointing.
A vaccine developed by Athena Neurosciences failed to improve patients' cognitive function in a trial that ended in 2002.
To better understand these results, a team of British scientists largely unaffiliated with Athena or the failed clinical trial decided to examine the brains of patients who had taken part in the study. They waited for the patients to die, then, after probing the brains, concluded that the vaccine had indeed cleared amyloid plaque but had not prevented further neuro-degeneration.
In 2004 TauRx began a clinical trial of its drug, called methylene blue, in 332 Alzheimer's patients.
About the same time, a drug maker called Elan Corp, which had bought Athena Neurosciences, began a trial of an amyloid-targeted drug called bapineuzumab in 234 patients.
A key moment came in 2008 when Wischik and Elan presented results of their studies at an Alzheimer's conference in Chicago.
The Elan drug failed to improve cognition any more than a placebo pill did and Elan shares plummeted by more than 60 per cent across the next few days.
The TauRx results Wischik presented were more positive, though not unequivocal. The study showed that after 50 weeks of treatment Alzheimer's patients taking a placebo had lost 7.8 points in a test of cognitive function, while people taking 60mg of TauRx's drug three times a day had lost only one. This amounted to an 87 per cent reduction in the rate of decline for people taking the TauRx drug.
But TauRx did not publish a full set of data from the trial and this led to some scepticism among researchers. (Wischik says it didn't protect the company's commercial interests.)
What's more, a higher, 100mg dose of the drug didn't produce the same positive effects in patients. Wischik blames this on the way the 100mg dose was formulated and says the company is testing a tweaked version of the drug in its new clinical trials, which will begin enrolling patients this year.
With its new clinical trial program under way, TauRx is the first company to test a tau-targeted drug against Alzheimer's in a large human study, known in the industry as a phase 3 trial.
Wischik admits he may be just as much a zealot about tau as he accuses others of being about beta amyloid. "I may be," he says. "In the end ... it's down to the phase three trial."
It wasn't easy. At the time, few organ banks kept entire brains.
But Wischik, an Australian who was in his early 30s at the time, was
trying to answer a riddle still puzzling the scientific community: what
causes Alzheimer's disease?To do that, he needed to examine brain tissue from Alzheimer's patients soon after death. That meant getting families' approval and enlisting mortuary technicians to extract the brains, he says, "no matter the time of day or night". And it wasn't just a few brains: he collected more than 300 across about a dozen years.
In his lifelong investigation, Wischik has backed a minority scientific view
that a protein called tau - which forms twisted fibres known as tangles inside the brain cells of Alzheimer's patients - is largely responsible for driving the disease.
For 20 years much of the scientific community, with billions of dollars of pharmaceutical investment, has supported a different theory that places chief blame on a different protein, beta amyloid, which forms sticky plaques in the brains of sufferers.
But a string of experimental drugs designed to attack beta amyloid has failed recently in clinical trials, and after years on the sidelines Wischik sees this as tau's big moment.
In the early 90s he and his colleagues compared the brains of Alzheimer's sufferers with those of people who died without dementia, to see how their levels of amyloid and tau differed.
They found healthy and Alzheimer's brains could be filled with amyloid plaque but only Alzheimer's brains contained aggregated tau.
What's more, as the levels of aggregated tau in a brain increased, so did the severity of dementia.
"We decided that amyloid isn't what is making people demented," Wischik says.
In the mid-90s he discovered that a drug sometimes used to treat psychosis dissolved tangles in a test tube.
He tried to set up a company to develop the drug as a treatment for Alzheimer's but found American and British venture capitalists wanted to invest in amyloid projects, not tau.
By 2002 he had scraped together $5 million from Asian investors with the help of a Singapore physician who was the father of a classmate of Wischik's son at Cambridge.
The company Wischik co-founded 10 years ago, TauRx Pharmaceuticals, is based in Singapore but conducts most of its research in Scotland, where he now lives. As his tau effort was launched, early tests of drugs designed to attack amyloid plaques were disappointing.
A vaccine developed by Athena Neurosciences failed to improve patients' cognitive function in a trial that ended in 2002.
To better understand these results, a team of British scientists largely unaffiliated with Athena or the failed clinical trial decided to examine the brains of patients who had taken part in the study. They waited for the patients to die, then, after probing the brains, concluded that the vaccine had indeed cleared amyloid plaque but had not prevented further neuro-degeneration.
In 2004 TauRx began a clinical trial of its drug, called methylene blue, in 332 Alzheimer's patients.
About the same time, a drug maker called Elan Corp, which had bought Athena Neurosciences, began a trial of an amyloid-targeted drug called bapineuzumab in 234 patients.
A key moment came in 2008 when Wischik and Elan presented results of their studies at an Alzheimer's conference in Chicago.
The Elan drug failed to improve cognition any more than a placebo pill did and Elan shares plummeted by more than 60 per cent across the next few days.
The TauRx results Wischik presented were more positive, though not unequivocal. The study showed that after 50 weeks of treatment Alzheimer's patients taking a placebo had lost 7.8 points in a test of cognitive function, while people taking 60mg of TauRx's drug three times a day had lost only one. This amounted to an 87 per cent reduction in the rate of decline for people taking the TauRx drug.
But TauRx did not publish a full set of data from the trial and this led to some scepticism among researchers. (Wischik says it didn't protect the company's commercial interests.)
What's more, a higher, 100mg dose of the drug didn't produce the same positive effects in patients. Wischik blames this on the way the 100mg dose was formulated and says the company is testing a tweaked version of the drug in its new clinical trials, which will begin enrolling patients this year.
With its new clinical trial program under way, TauRx is the first company to test a tau-targeted drug against Alzheimer's in a large human study, known in the industry as a phase 3 trial.
Wischik admits he may be just as much a zealot about tau as he accuses others of being about beta amyloid. "I may be," he says. "In the end ... it's down to the phase three trial."
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