For the first time, researchers have created a molecule that provides long-lasting preventative protection against toxic nerve agents in rodents. Their new study describing the molecule's potential was published in the January 2 issue of Science Translational Medicine.
Their treatment strategy represents a breakthrough in the field of nerve agent poisoning, as researchers have unsuccessfully spent 60 years in search of similar approaches. Although more testing is necessary before human trials can be conducted, the therapy could one day help shield at-risk individuals from nerve agents, many of which are used in chemical warfare and as pesticides.
The scientists imagine a scenario where a refined version of their compound could be administered to soldiers or civilians before they encounter situations where chemical weapons like sarin are likely to be deployed.
Organophosphates are a family of chemicals that block the communication between nerves and organs, causing muscle paralysis and death within minutes due to impaired breathing. Their high toxicity makes them very useful as pesticides. However, pesticides containing organophosphates are still toxic to humans — one study estimated they cause 200,000 poisoning deaths a year in developing countries.
Furthermore, organophosphates have been repurposed into extremely toxic nerve agents such as sarin and VX. These lethal poisons have been used in terrorist attacks such as the Tokyo subway attack in 1996 and in conflicts such as the ongoing Syrian Civil War .
Sarin and other nerve agents can cause death within minutes when inhaled or exposed to human skin, making it difficult to successfully treat affected patients. Existing therapies must be administered within hours or minutes to be effective, and they do not protect patients from severe side effects such as convulsions and permanent brain damage, according to the Science authors.
"Nerve agents threaten both soldiers and civilians in war zones while organophosphate poisoning remains a major medical issue for public health," said Shaoyi Jiang, professor of chemical engineering at the University of Washington in Seattle, Washington and senior author of the new study. "The acute nature of the poisoning demands effective therapeutic and [preventative] interventions."
For decades, researchers have sought to create a preventative treatment based on a "bioscavenger" — a compound that breaks down organophosphates in the bloodstream before they reach the nervous system. Administering such a treatment before nerve agent exposure could avoid permanent damage and bypass the need for fast-acting post-exposure antidotes, said Jiang.
Despite their potential, existing bioscavenger candidates in development have only provided protection for a few hours in animal models. Furthermore, some of the most promising formulations provoke undesirable responses from the immune system, according to Jiang.
To overcome these obstacles, Peng Zhang and colleagues developed a bioscavenger based on an enzyme named OPH, which can decompose nerve agents into biologically harmless molecules. Critically, the researchers encased the enzyme in a tiny capsule made of polymers that prevents it from being recognized by the immune system.
As a result, the capsule "dramatically" prolongs the time that the bioscavenger remains in the blood and makes long-term preventative protection feasible, according to Jiang.
The scientists conducted several experiments to determine how well their compound worked in rodents. A single intravenous treatment protected rats against a lethal injection of the organophosphate paraoxon — an ingredient of the insecticide parathion — for seven days. The compound also prevented poisoning in rats that had received a paraoxon injection immediately before treatment.
To mirror what individuals might encounter in a conflict zone or other military setting, the group also investigated whether their treatment could protect animals against multiple exposures to nerve agents. They intravenously administered the bioscavenger to guinea pigs, waited 20 minutes, and injected the animals with a lethal dose of sarin. The animals then received an additional sarin injection every 24 hours.
The bioscavenger provided safe and near-total protection against the sarin injections. All the guinea pigs that received the treatment showed no signs of poisoning after eight days of daily injections (the equivalent of weeks to a month in humans). By contrast, guinea pigs in the control group that received OPH without the protective capsule did not survive after the third day.
"As a breakthrough, a one-week preventative protection time window was achieved against sarin, while previous bioscavengers mostly protect victims within hours post administration," Jiang said.
One limitation of the study is that the scavenger was only active against G-type agents, a category of nerve agents that includes sarin. The researchers plan to conduct further studies to develop enzymes that can counteract the effects of other types of nerve agents such as the V-type category, which includes VX.
Further research is also necessary to determine the compound's long-term efficacy and safety in a large animal model such as monkeys. However, Jiang's team believes that the long-lasting nature of their treatment in rodents signifies it could help fulfill unmet needs in both medical and military applications.
"Since the vascular [or in blood vessels] residence time of modified proteins in humans can be several-fold longer than in rodents, it is hoped that the protection time window will prove to be several weeks to a month in human prophylactic applications to fulfill the mission of bioscavengers," he said.