Venom of marine cone snails may provide an improved treatment for neuropathic pain associated with diabetes

Jun 12 2005

A cone snail toxin discovered by Melbourne researchers has proven to have great potential for easing pain and could provide an improved treatment for neuropathic pain associated with diabetes.

Melbourne based company Metabolic Pharmaceuticals Limited recently announced successful results in preclinical trials of the toxin. The company will begin clinical trials in humans this month to firstly test the safety of the toxin in normal males, and later its effectiveness in treating the neuropathic pain associated with diabetes.

From the University of Melbourne’s Department of Biochemistry and Molecular Biology and the recently launched Bio21 Institute, Associate Professor Bruce Livett says the toxin – called ACV1 – also has potential for treating a range of other painful conditions, such as multiple sclerosis, shingles and sciatica.

“ACV1 has been shown to be effective in treating pain in several experimental animal models of human pain syndromes, including post-surgical and neuropathic pain,” Associate Professor Livett says.

“In addition, it has the unique property that it appears to accelerate the rate of recovery from a nerve injury.”

“We are very excited that clinical trials to test the effectiveness of ACV1 in humans with diabetic neuropathies will soon be underway and we expect that the potential of ACV1 in treating a range of other painful conditions will also be realised in time.”

ACV1 has shown potential for treating neuropathic pain, that is, pain generated inside the body (arising in the nervous system) as opposed to the other type of pain – nociceptive pain – which comes from the outside in, for example, a burn.

Associate Professor Livett says neuropathic pain is the most difficult form to treat and typically responds poorly to conventional painkillers such as morphine or aspirin. Other treatments have also been found to be largely ineffective.

The great potential of ACV1 is that eliminating neuropathic pain is where it works best.

Associate Professor Livett and his colleagues first discovered ACV1 in 2003 while studying the toxins produced in the venom of Conus victoriae, a marine cone snail found in tropical waters off the coast of Australia.

All cone snails produce venom which they use to paralyse prey before killing and eating them. The venom of some cone snails is toxic to humans – as many as 30 people are known to have died from cone snail envenomation.

The cone snails that are dangerous to humans feed on fish by impaling them with a harpoon styled barb (a modified tooth called a radula) loaded with toxic venom.

Associate Professor Livett says there are up to 200 components in each venom and there are over 500 species of cone snail, each with a different cocktail of venom peptides. Fortunately, most cone snails hunt marine worms or other molluscs and are not harmful to humans.

It may seem unusual that toxic venoms can also be a source of pain relieving medication for humans.

Associate Professor Livett explains, “It appears that cone snails have adopted the general strategy of including a pain-reducing component among the more lethal components of its venom.”

“That is, it first pacifies its victim before immobilising and eventually killing it. Witnesses to cone snail envenomation report that death by cone snail poisoning is seemingly painless.”

It is this special pain-reducing component that the researchers have been interested in.

The Melbourne team, which includes Associate Professors Bruce Livett and Ken Gayler and Dr John Down from the Department of Biochemistry and Molecular Biology, Associate Professor Zeinab Khalil from the University’s National Ageing Research Institute, and research students Mr David Sandall, Mr David Keays and Ms Narmatha Satkunanathan, were the first to isolate and characterise ACV1.

It was a true collaborative venture starting with genes discovered by Associate Professor Gayler, Mr Sandall and Mr Keays, capitalizing on the pharmacological and chemical expertise of Associate Professor Livett and Dr Down, marrying with the physiological and pain assessment expertise of Associate Professor Khalil.

ACV1 is not the only therapeutic compound that cone snail venom has to offer. In fact, the venom is a cocktail of thousands of biologically active compounds of which only a few hundred have been identified.

Associate Professor Gayler says the team, by using genes as the starting point, are able to minimize the number of cone snails required to develop new tools and therapies for medical research and therefore minimise the environmental impact of the research. “With a single cone snail we can create and store large libraries of conotoxin genes.”

It was using this genetic mining technique that ACV1 was discovered – its peptide sequence was predicted solely from the DNA sequence. The peptide was then chemically synthesised in large quantities suitable for biological testing. This same approach is now being used by Metabolic Pharmaceuticals to synthesise gram amounts of ACV1 needed for the planned human clinical trials for diabetic neuropathy.

“With an increasing age demographic in our society the need for more effective pain suppressing compounds is a priority. ACV1 may fill this unmet need,” Associate Professor Livett says.