Development of Delivery Vehicle Targeting Cholinergic

Period of Performance: 06/12/2000 - 11/11/2002

$458K

Phase 2 STTR

Recipient Firm

Metabiologics, Inc.
505 S. Rosa Rd.
Madison, WI 53719
Principal Investigator

Research Institution

University of Wisconsin, Madison
2100 Main Street
Madison, WI 53706
Institution POC

Abstract

The seven toxin serotypes of Clostridium botulinum neurotoxin are the most potent substances known to mankind. The neurotoxins act on cholinergic neurons inhibiting the release of acetylycholine causing flaccid paralysis due to the inability of the enervated muscle to contract At present there is no known treatment for non-immunized individuals exposed to the toxin as once the active portion of the toxin is internalized into the neuron antibodies to the toxin are no longer beneficial. Research under this proposal will demonstrate the feasibility of synthesizing prodrugs consisting of multiple copies of the model metalloprotease inhibitor captopril covalently bound to a polymeric delivery vehicle which will be directly linked to botulinurm heavy chain. This will yield a pharmaceutically active compound that specifically targets and internalizes desired substances into cholinergic neurons including inhibitors of the active fragment of the neurotoxin itself. Phase II research will consist of synthesis of prodrug conjugates and assessment of their internalization into cultured motor neurons and neurons associated with other in vitro models. Potential benefits stemming from this research and additional work being done at the University of Wisconsin include the following; 1. Antidotes to botulinal neurotoxins will be synthesized for civilians and U.S. military personnel lacking immunizations that have been exposed to toxins. 2. The delivery vehicles generated under this research could be used to transport other pharmaceuticals of interest that lack either water solubility, CNS toxicity, or are degraded rapidly specifically to motor neurons.