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Pakistani firewalker boy’s gene could lead to best – and safest – of pain drugs ever

Friday, June 26, 2009, 6:18 This news item was posted in Extra, Featured category and has 0 Comments so far.

Ralfinamide from Newron, which promises the least side-effects, is on way; Pfizer, AstraZeneca & Merck are exploring potential drugs to block the Nav1.7 channel.

A defective gene from a Pakistani firewalker boy has provided clues to drug researchers to unlock the secret of pain pathways that could lead to perhaps the most effective and the safest pain drug ever in existence.

John Wood, a geneticist at the University of Cambridge found a defect in the gene which made the boy insensitive to physical pain as he walked over burning coal or pushed the blade of a knife painlessly through his arm, while performing street stunts in northern Pakistan.

The defective gene was detected among other children as well belonging to the same area in Pakistan leading to the conclusion that the particular gene ran in families. All the children where otherwise healthy with normal sense of touch.

Identification of this faulty gene opened an altogether new area of pain research among drug makers.

The gene, known as SCN9A, produces a protein called Nav1.7, one of ten proteins that make up the sodium channels that dot the surface of axons and help propagate neural signals. Nav1.7 is found in specialized sensory fibers that respond to pain signals from throughout the body and transmit them to the spinal cord and brain.

The sensation of pain is produced when a noxious stimulus depolarizes receptors in the skin and other organs that send pain signals to the spinal cord and brain. Because pain signals follow their own pathways to the brain, the family members in Pakistan are able to perceive nonpainful sensations normally. When the sensation would become painful to most people, they continue to perceive it as normal because their pain pathways are inoperative due to the mutation in the gene SCN9A.

The pain-free Pakistani family did have sodium channels in their pain receptors, but those channels were inactive because of the mutation affecting the Nav1.7 protein.

The led scientists to reach the conclusion that a drug that blocks those channels should provide pain relief. However, they are very cautioned. Blocking of sodium channels are very dangerous. So they need to be inhibited very selectively.

“It’s the ultimate target,” said John Wood, a professor of molecular neurobiology at University College London. “The people that don’t have the channel are not ill, they have no problems, so if you find a drug that blocks it, they should be pain-free and also free of side effects.”

Ralfinamide from Newron to herald the new era of painkillers?

Taking the clue, several innovative drugs are in development that can selectively block the Nav1.7 sodium channel and alleviate pain. Newron Pharmaceuticals SpA of Italy has developed a product that blocks Nav1.7 sodium channel. The drug named ralfinamide is in the last stage of human testing. The Milan-based company is testing ralfinamide in about 400 patients participating in Austria, Germany, India, Italy, Romania and the U.K. Results are due in the first half of 2010.

Ralfinamide acts on more than one chemical pathway to pain and in the meantime, it doesn’t completely shut the sodium 1.7 channel.

Besides inhibiting several sodium channels, including the Nav1.7, Ralfinamide acts on calcium channels, which play a similar role in signaling pain. The drug also controls the release of a chemical messenger called Substance P.

Newron will market ralfinamide for neuropathic lower back pain, which is caused by damage to the nervous system. Newron plans to seek regulatory approval in 2012.

Among the drug giants, Pfizer is developing compounds that block the sodium 1.7 channel. AstraZeneca Plc and Merck & Co are planning to study drugs that work like the gene mutations by interrupting a channel that transmits pain signals.

Pain killers one of the largest segment in pharmaceuticals. In 2007 painkillers generated $24.3 billion in sales, according to London-based Datamonitor Plc.

Though the pain drugs market is flooded with a number of drugs, most of them have serious and often dangerous side-effects. The class of non- steroidal anti-inflammatory drugs (NSAIDS), that includes aspirin and ibuprofen, can cause irritation in the stomach. Opioids, which include drugs like morphine, are derived from the opium poppy and, are among the most- abused prescription medicines. Some of the new generation pain drugs like Merck’s Vioxx has been withdrawn from the market because of a potential link to heart attacks and strokes.

Professor John Wood: The Pioneer

John Wood, professor of Molecular Neurobiology at the UCL Wolfson Institute for Biomedical Science (WIBR), has been a neuroscience researcher for nearly 30 years. He is a principal investigator in the London Pain Consortium, and a participant in the World Class University Professor scheme of  Seoul National University in South Korea. He has won the Grand Prix Scientifique 2009 from the Fondation NRJ, at  the Institut de France.

The annual prize is open to research teams across Europe. The theme this year was ‘pain and its treatments’.

In 2002, he co-founded Ionix pharmaceuticals, a start-up biotechnology company recently acquired by Vernalis that is based in Cambridge, UK, with the aim of developing  analgesic drugs directed against new targets defined by genetic research. Dr Wood is the author of more than a hundred research publications, and several books and patents.

Woods’s work, funded by Pfizer, the University of Cambridge and the London-based Wellcome Trust, was the first to establish a link between loss of the channel and an absence of distress.

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