ACV1 effective in treating neuropathic pain - research update from Cone shells

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ACV1 effective in treating neuropathic pain - research update from Cone shells

Molecular miners find pain relief drugs from the sea

11 Jun 2005 Medical News Today

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.

BACKGROUND

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 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 Sandall, Mr 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.

University of Melbourne

unimelb.edu.au