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Edging closer to a cure for Alzheimer’s

With millions of sufferers worldwide, Alzheimer's disease – the most common form of dementia – represents one of the biggest and potentially lucrative challenges in modern medical research.

For AstraZeneca, a company desperate to find a new generation of treatments to replenish its dwindling stock of patented drugs, it represents a serious commercial opportunity.

Spurred on by a new chief executive, Pascal Soriot, who was brought in to turn around Britain's second-biggest drug firm after a shareholder revolt, AstraZeneca's team of 40 brain researchers are spread between labs in Cambridge in the United Kingdom and Cambridge in Massachusetts in the United States. They are working with academics and biotech firms to develop treatments for schizophrenia, Parkinson's and chronic pain. The company is also hiring hundreds of scientists to boost its 300-strong research team in China.

Other drugmakers, including GlaxoSmithKline, have pulled out of neuroscience altogether. But AstraZeneca – set to lose patent protection on 50% of its revenue in the next five years – has given its scientists a deadline of three years to devise novel treatments in this ­notoriously difficult field. AstraZeneca's first neuroscience drug to reach late-stage clinical ­trials is not for dementia but for pain relief.

"There have been no new approvals for a completely novel treatment for treating pain over the past decade," said Iain Chessell, AstraZeneca's vice-president of research and development in neuroscience. "If you are one of the one in three who will suffer from chronic pain, there is at best a 50% chance to get treatment."

The Alzheimer's drugs on the market merely treat the symptoms, such as memory loss and mood swings. But the competition is hotting up in the pursuit of the bigger prize.

A group of scientists at the Korea National Institute of Health had found a protein that contributes to the cause of Alzheimer's, it was announced on Monday. The protein, called Sumo-1, triggered the creation of beta-amyloid peptide, a toxic ­substance that is believed to cause the disease.

Toxic effect
In August, rivals in the US unveiled a pill that could become one of the first treatments actually to slow or stop Alzheimer's. The rival new pill, using a natural chemical found in pine cones, is being developed by the US drug researcher Humanetics and the Mount Sinai School of Medicine in New York. A daily tablet, it is based on a widely held theory that a major cause of the disease is "amyloid plaques" – fibrous proteins that coat the cells of the brain.

The Humanetics pill prevents the plaques from forming and AstraZeneca's scientists, working in partnership with Axerion, a private biotech firm in Connecticut, are trying to develop a medicine to block their toxic effect.

Sylvia McBrinn, chief executive of Axerion, said in May that the hope was to produce a "novel therapy that works quite differently from the Alzheimer's drug candidates in development".

However, the "amyloid theory" has had some setbacks recently. US rival Eli Lilly's experimental Alzheimer's drug, which aims to reduce amyloid protein in the brain, failed its main clinical trial goals, although it did show a significant slowing of cognitive decline in patients with mild to moderate Alzheimer's.

One of the main difficulties that drug treatments for the brain have to overcome is the "blood-brain barrier" – the make-up of the brain's blood supply protects it from most infection, but that also keeps out larger molecules such as antibiotics and antibodies.

"Blood-brain barrier penetration is the holy grail" for diseases such as Alzheimer's, said Jane Osbourn, site leader for AstraZeneca's biologics arm MedImmune, based in Cambridge in Britain.

Blue coats only
As she talked, we entered the Cambridge lab through a door labelled "blue coats only". This is where the drug giant develops many of its biological drugs, which include antibodies and vaccines. The colour of the coat denotes the hazard level: blue is worn by visitors.

When AstraZeneca bought MedImmune, a biotechnology firm based in Maryland, in 2007, 300 people worked in the Cambridge lab. The number has since risen to 550. The $15.6-billion deal – the biggest acquisition made by AstraZeneca's former boss, David Brennan – gave the drugmaker much-needed expertise in biological medicines.

Biological treatments are made from genetically engineered versions of human proteins, such as antibodies; the active ingredients are several hundred times larger than the compounds found in chemical pills. An antibody is 1000 times larger than paracetamol, for instance. Scientists sometimes compare a small molecule to a skateboard and a large mole­cule to a jumbo jet. Hence the talk of blood-brain barriers.

The Cambridge lab has a huge library of 100-billion antibodies. John Elvin, who has spent 17 years in the industry and worked for Cambridge Antibody Technology, which AstraZeneca took over in 2006, said: "Somewhere in this library there could be a blockbuster." To screen them all one at a time would take 30 years.

But the appeal of antibodies is that, because the body's own immune system produces them to fight a specific infection, they are precisely targeted – they rarely produce a cross-reaction, that is to say, they will not hit something else. The cost of production has come down dramatically, but it is still much greater than for small molecules.

"We are very confident we can get antibodies with the right specificity," said Osbourn. "Where things get more unpredictable is when we start using the antibodies to understand the biology of the disease we are interested in."

Much of the lab work is automated, including all of the selection, screening and washing processes. A camera images a plate with bacterial colonies and automated pins pick out "good clean colonies" and transfer them on to a new plate. Elvin said: "When I was a wee lad we would pick them out by hand. It would take hours. We had the radio on. Now it takes just a couple of minutes."

Elvin said he had that "amazing feeling of 'My goodness, it works' a handful of times" during his career. With billions of molecules to work through, perhaps he is due to get that feeling again. – © Guardian News & Media 2012

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