Summary

Organophosphorous nerve agents represent a very real threat not only to warfighters in the field but also to the public at large.82 Nerve agents have already been used by terrorist groups against a civilian population and, due to their low cost and relative ease of synthesis, are likely to be used again in the future.83 In addition, many commonly used pesticides and chemical manufacturing by-products can act as anti-cholinesterases, and may be a low-dose exposure threat to workers in a variety of professions. Current therapeutic regimes for acute nerve agent exposure are generally effective at preventing fatalities if administered in an appropriate time frame. While the current therapeutic drugs, atropine and 2-PAM, have not been tested against a low-level exposure, their requirement for timely administration following symptoms makes it unclear whether under low-level exposure conditions these therapeutic interventions could be effectively implemented on a large scale. For acute multi-LD50 levels of exposure, pyridostigmine pretreatment coupled with post-exposure administration of an oxime, atropine, and an anti-convulsant does not prevent the substantial behavioral incapacitation or, in some cases, permanent brain damage that can result from OP poisoning. For low-level exposures that result in the Level 1 or Level 2 effects described above, the current therapy will probably not be administered at all since it is to be given at the onset of overt physiological signs. It is therefore important from both military and domestic security perspectives to develop novel defenses against nerve agents, including the use of bioscavenger molecules that avoid many of the difficulties associated with current treatments. While the use of nerve agents on the battlefield may be somewhat predictable, their use in a terrorist situation will be, in all probability, an unanticipatable event. The ability to afford long-term protection for first-responders exposed to toxic, incapacitating or Level 3 doses of OP, thereby reducing the severity of outcomes to Level 2 or Level 1 symptoms (and eliminating the impact of Level 1 and 2 exposures completely), is a notable potential advantage of biological scavengers.

The use of bioscavengers as a defense against OP intoxication has many advantages and few apparent disadvantages. As discussed in detail above, bioscavengers can afford protection against not only mortality, but also most or all of the adverse physiological and behavioral effects of nerve agent exposure. They can be administered prophylactically, precluding the need for immediate post-exposure treatment. In addition, the use of bioscavengers has several psychological benefits that are likely to result in a higher degree of user acceptability than exists for conventional therapy. No post-exposure auto-injectors are necessary, and protection is afforded with little chance of short- or long-term side effects. Of particular significance is the fact that current candidate bioscavenger proteins are, for the most part, enzymes of human origin. From a scientific standpoint, these proteins are good candidates because they are less likely to be recognized by cells of the immune system, and will enjoy prolonged residence times in circulation. From a user point of view, individuals are, in essence, being protected against nerve agents using a substance that their bodies already produce, rather than being injected with drugs and enzyme inhibitors that alone can produce potent side effects; such a distinction may enhance the comfort and compliance of end users.

There are several challenges that must be met in the future before bioscavengers can augment or replace the current therapeutic regimes for nerve agent intoxication. First, scavenger proteins, either alone or in combination, with a range of specificities that encompasses all known nerve agents, must be defined. The immunogenicity and serum half-life of the scavenger(s) must be determined in humans, and efforts may be required to minimize the former and maximize the latter. Finally, appropriate dosages of scavenger(s) must be determined that will, based on animal models, protect against concentrations of nerve agents likely to be encountered under a wide range of scenarios. While the majority of the research to date has focused on stoichiometric scavengers, the use of either naturally occurring or genetically engineered enzymes with catalytic activity holds the greatest theoretical promise for the development of a broad specificity prophylactic scavenger. Future efforts are likely to focus on generating, characterizing, and utilizing such enzymes in rodent and non-human primate models.

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