DEVELOPMENT OF AN ORAL CARRIER
Principal Investigator: LANCE SIMPSON
Affiliation: Thomas Jefferson University
Abstract: 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.
Funding Period: 1999-01-01 - 2002-02-28
more information: NIH RePORT
- Visualization of binding and transcytosis of botulinum toxin by human intestinal epithelial cellsChowdhury R Ahsan
Department of Medicine, Jefferson Medical College, Room 314-JAH, 1020 Locust Street, Philadelphia, PA 19107, USA
J Pharmacol Exp Ther 315:1028-35. 2005..Transcytosed toxin began to reach the contralateral surface within ca. 5 min, and transcytosis was essentially complete within 20 to 30 min...
- An initial assessment of the systemic pharmacokinetics of botulinum toxinEaswaran Ravichandran
Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA
J Pharmacol Exp Ther 318:1343-51. 2006..This work demonstrated that neutralizing antibodies 1) enhanced clearance of toxin from the circulation and 2) enhanced tissue accumulation of toxin, particularly in liver and spleen...
- Trivalent vaccine against botulinum toxin serotypes A, B, and E that can be administered by the mucosal routeEaswaran Ravichandran
Department of Medicine, Jefferson Medical College, 1020 Locust Street, Philadelphia, PA 19107, USA
Infect Immun 75:3043-54. 2007..These results are a compelling demonstration that a mucosal vaccine against multiple serotypes of botulinum toxin has been identified...