January 3, 2019

expert reaction to study looking to develop a scavenging molecule to protect against nerve agent poisoning in rats

Research published in Science Translational Medicine demonstrates the use of a molecule that provides resistance to nerve agent poisoning in rats.

Prof Alastair Hay, Professor Emeritus of Environmental Toxicology, University of Leeds, said:

“This paper on the nanoscavenger is very promising and the work has been done well.

“As the authors point out current processes for clearing OP (organophosphate) agents from the circulation are limited by a range of factors, but particularly the amount of agent that can be removed by in vivo clearance agents already present in the circulation, such as the enzyme butrylcholinesterase (BuChe).  Once BuChe binds to the OP it is put out of action and you have to wait for more BuChe to be produced by the liver.  BuChe can be administered intravenously but in limited amounts.

“What you require, as the authors point out, is something circulating which mops up any free circulating OP to prevent this entering the nervous system and the brain in particular.  The nano formulation they have developed appears to overcome many of the limitations of existing therapeutic agents.  The nano product has a long residence time in blood, is stable, and effective against repeated exposures to OPs.  Thus it has potential for treating those poisoned, but also acting as a prophylactic for those who may have to handle OPs, such as pesticide applicators working in agricultural settings or those who manufacture the chemicals.

“The authors are also clear about the limitations of their product.  Their product is an enzyme which hydrolyses (breaks down) OPs and to provide it with staying power they have coated it with a highly charged (with both positive and negative ions) polymer.  This coating both protects the active site of the enzyme, but also provides protection against the body’s normal clearance mechanisms for proteins, as the engineered product is not taken into cells readily nor filtered easily by the kidney.

“One of the risks for injected biomolecules, but an essential feature of nature’s defences against invading biological agents, is the immune response.  Foreign biomolecules trigger our defences to provide antibodies to neutralise the invaders.  This process could rapidly inactivate therapeutic biomolecules injected to increase breakdown of OPs.  However, in this case the engineered nanoparticle appears not to trigger a massive immune response thereby allowing the particle to stay effective for a long time.

“This resistance to breakdown is a feature that will have to be explored in great detail to assess the long-term health implications of injecting a non-degradable biopolymer into poisoned victims.  So there is much testing still to be done before the agent might be used in humans.

“It would also help if the authors used another acronym other than PCB for their poly(carboxybetaine) polymer to distinguish it from polychlorobiphenyls (a completely different structure) and which would be a ‘No-No’ for injecting into humans.

“But the really positive message of this research is that a process has been developed which offers huge potential for both treating OP poisoned victims, but also protecting those (prophylactically) who may use OPs on a day-to-day basis in their work.

“Future research will investigate different polymers (perhaps more biodegradable, but equally effective) and engineered enzymes that will degrade the full range of organophosphate nerve agents.  The product described in this paper will degrade what are known as G agents (such as sarin used in wars in Iraq and to poison many in Syria) but not the V agents (like VX used to assassinate the North Korean leader’s half brother in Malaysia).”

‘Nanoscavenger provides long-term prophylactic protection against nerve agents in rodents’ by Peng Zhang et al. was published in Science Translational Medicine at 19:00 UK time on Wednesday 2 January 2019.

Declared interests

None received.