Despite international bans, some countries, such as Syria, use deadly nerve agents against enemy soldiers and civilians. Existing treatments for these chemical weapon attacks must be given quickly and don’t always prevent convulsions or brain damage. Now, U.S. Army researchers have created a gene therapy that allows mice to make their own nerve agent–busting proteins, providing protection against the toxicants for months.
The strategy could theoretically be adopted for human soldiers, but it would have risks. A person could develop a harmful immune response to the introduced protein, for example. “There are a number of pros and cons,” says biochemist Moshe Goldsmith of the Weizmann Institute of Science, who was not involved with the research.
Nerve agents are chemicals known as organophosphates. The most commonly used type includes sarin, soman, cyclosarin, and tabun. All block an enzyme that regulates levels of the neurotransmitter acetylcholine in muscles, causing muscle spasms, difficulty breathing, and sometimes death. Current treatments, such as atropine and diazepam, work by blocking acetylcholine receptors, but they must be administered right away and can’t always prevent permanent neurological damage.
Seeking a better solution, some researchers have injected lab animals with sped-up versions of human enzymes that spur organophosphates to break down before they can cause damage. For example, Goldsmith and collaborators have tweaked an enzyme called paraoxonase 1 (PON1) so that it can help the body defang nerve agents faster. But doctors would need to inject a massive quantity of such “bioscavengers” into the bloodstream or find a way to shield the proteins from the immune system for them to be effective.
So scientists at the U.S. Army Medical Research Institute of Chemical Defense took a different approach: Turn the liver into a factory for making a bioscavenger enzyme. Led by biochemist Nageswararao Chilukuri, they used a harmless virus called an adeno-associated virus to ferry DNA instructions into the liver cells of mice. The result was the mice’s liver cells cranking out a potent version of PON1.
Mice injected with the DNA-ferrying virus soon had high blood levels of the synthetic PON1 enzyme, which remained stable for the 5-month study. The rodents survived nine normally lethal injections of nerve agents over 6 weeks, the Army team reports today in Science Translational Medicine.
“We were surprised by how well this protein is expressed and how long it lasted,” Chilukuri says. The team also showed the PON1 levels were just as high when the treatment was injected into muscles, a more practical delivery method on the battlefield.
The gene therapy seemed to cause no harm to the mice. And although the animals made antibodies against the foreign PON1 protein, indicating an immune response, the antibody levels were too low to mute the protein’s activity against nerve agents. Chilukuri’ s team suggests the therapy could protect soldiers, first responder medical staff, and military dogs, and could also protect farm workers at risk of being exposed to organophosphate pesticides. These are less toxic than nerve agents but can cause similar health effects at high doses.
“It’s a very nice paper, a nice advance in the field,” says biochemist Oksana Lockridge of the University of Nebraska, Lincoln. But she and others caution that the revved-up PON1—which contains parts of the rabbit, rodent, and human versions of PON1—is likely to provoke a stronger immune response in people, which could dull its effectiveness or cause severe health effects. People receiving the therapy might even make antibodies against standard human PON1, which the body uses to process harmful cholesterol, and could end up with an elevated risk of heart disease, Goldsmith says.
Chilukuri acknowledges the caveats but notes his team didn’t set out to solve all possible problems with the therapy. “It’s kind of a proof of principle study,” he says. “This is one way to keep the bioscavenger working for weeks and months in an animal.”
Source: Science Mag