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Abstract:
Project Summary: The long-term objective of this effort is to develop a generic gene shuff-ling-based technology to rapidly screen libraries of 1010 proteins/peptides encoded by DNA libraries, for identifying biomolecules that can intercept both existing and emerging organophosphate- based chemical warfare nerve agents (CWNA). All 5th year milestones have been met: (a) Determine the protective efficacy of 3 PON1 variants in a guinea pig model against GD, GF and GA as compared to untreated animals. Success Criteria: 48hr survival of greater than 90% of the animals tested with 3 nerve agents versus untreated animals. (b) Develop a revised mathematical model to estimate an efficacious dose of a PON1 variant in humans. Success Criteria: Validation of the model against existing guinea pig in vivo efficacy data. (c) Develop at least one PON1 variant with enhanced in vitro and in vivo V-agent activity. Success Criteria: In vitro: a 50 fold increase in hydrolysis of the P- isomer relative to hydrolysis of P (-) VX by 4E9. In vivo: Protection against a 2xLD50 exposure to a V agent in a guinea pig model, as mediated by a 10 mg/kg or lower dose of enzyme administered as a pretreatment. When successful, candidate variants will be used to establish a model to determine in vivo post-exposure efficacy. Relevance: This technology is envisaged to provide rapid discovery of pretreatment and post challenge therapeutic drugs against existing & emerging CWNA threats and will shorten the time from emergence of a threat to identification of potential counter-measures to a few days or weeks.
| Limitations: |
 APPROVED FOR PUBLIC RELEASE |
| Description: |
Annual rept. 29 Jan 2010-31 May 2011 |
| Pages: |
17 |
| Report Date: |
Jun 2011 |
| Contract Number: |
W81XWH-07-2-0020 |
| Report Number: |
A198255 |
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Keywords relating to this report:
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