The long-term objective of the proposed research is to develop a novel strategy for creating drugs that can be administered by the oral route. This strategy will utilize a naturally occurring substance known as botulinum toxin, which is the etiologic agent responsible for the disease botulism. Under normal circumstances, this toxin is ingested during episodes of food poisoning. Ingested toxin escapes from the gut to reach the general circulation, and from here it is distributed to vulnerable cells throughout the body. In the recent past, two discoveries have been made about botulinum toxin. First, the toxin binds to, and is transported across, gut cells. This may be the mechanism by which the toxin escapes the gastrointestinal system to reach the general circulation. Second, the techniques of molecular biology can be used to create a modified version of the toxin that retains the ability to escape from the gut but has lost the ability to poison cells. This modified version of the toxin has been shown to be an oral vaccine against botulism.
The specific aim of the proposed research is to test the possibility that modified botulinum toxin can be used as a carrier to transport drugs from the gut to the general circulation.
This specific aim will be accomplished by pursuing three related areas of research. First, the techniques of molecular biology will be used to express polypeptide fragments of botulinum toxin that can act as carriers. Next, in vivo experiments will be done on laboratory animals to ensure that potential carriers actually transport drugs from the gastrointestinal system to the general circulation. Finally, in vitro experiments will be done on human gut cells in culture to determine whether the carriers are likely to act in human patients. If the carrier strategy is successful, it could be applied to the creation of several oral vaccines. Furthermore, it may be possible that for each vaccine the peptide carrier (viz., modified recombinant botulinum toxin) and the peptide antigen (viz., recombinant vaccine) could be generated as the expression product of a single chimeric gene.
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