When Claude Wischik arrived at Cambridge University in 1980 to do a Ph.D. under Professor Sir Martin Roth, scientists around the world were trying to work out the cause of Alzheimer’s – a disease that affects tens of millions, but for which no effective treatment exists.
Dr. Alois Alzheimer, who first described the disease in 1906, had identified thick fiber tangles in the brains of sufferers. Decades later, Roth established a correlation between the formation of tangles and the degree of dementia. He gave Wischik the task of finding out what the tangles were.
Wischik, born in France and raised in Australia, did not set out to play a pivotal role in Alzheimer’s research. His first degree was in mathematics and philosophy. He only came to medicine, he says, because meeting his wife-to-be made it clear to him he “needed a proper job”. “The trouble was,” he says, “I found myself becoming increasingly interested”.
Working in the lab at Cambridge, Wischik had to isolate the tangle before he could identify it. Colleagues suggested using the dyes alcian blue and dimethyl-methylene blue on the samples. To Wischik’s surprise, they blew the tangle fibres apart. As unexpected as this was, it gave him the idea – if you could create a drug that would dissolve the tangle, could this be the basis of a treatment for Alzheimer’s? “I was intrigued,” he says. “I spent a night in the library looking up compounds. That’s when I hit upon methylene blue. The key was, it also dissolved the tangles and had already been used psychiatrically – that meant it got into the brain.”
Wischik discovered that the tangles are made of tau, a protein normally present in the brain but which, in Alzheimer’s patients, folds back on itself and aggregates into oligomers which propagate themselves. His hope was that he had found a way to prevent tau aggregation. The theory now had to be put to the test.
Together with investors, he founded the company TauRx and set about launching a phase 2 clinical trial. By now, he had taken up the Chair of Mental Health at Aberdeen University, in Scotland. Here he met organic chemist, Professor John Storey. “Storey’s role was crucial,” explains Wischik. “Methylene blue is a fairly impure dye. Although it had been used as a pharmaceutical, it had not been manufactured to the standard required for long-term dosing. With Storey’s help, we were able to create a suitably pure form, called rember®.”
The phase 2 trial results were impressive: The drug arrested the progression of Alzheimer’s for two years. The team is now carrying out a global phase 3 trial, this time using a novel stable, reduced form of the drug, called LMTX™, that is more easily absorbed and better tolerated.
“Methylene blue is the scaffolding we used to get to where we are,” says Wischik. “Our hope is that LMTX™ will be the first disease-modifying treatment of Alzheimer’s.”