Targeted Paraoxonase Fusion Protein as a Neurotherapeutic for Nerve Gas Agents

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$1,951,120.00
Award Year:
2006
Program:
SBIR
Phase:
Phase I
Contract:
1U44NS057843-01
Agency Tracking Number:
NS057843
Solicitation Year:
2006
Solicitation Topic Code:
n/a
Solicitation Number:
PHS2006-2
Small Business Information
ARMAGEN TECHNOLOGIES, INC.
ARMAGEN TECHNOLOGIES, INC., 914 COLORADO AVE, SANTA MONICA, CA, 90401
Hubzone Owned:
N
Socially and Economically Disadvantaged:
N
Woman Owned:
N
Duns:
n/a
Principal Investigator:
YUFENG ZHANG
(310) 917-1275
yzhang@armagen.com
Business Contact:
JENNIFER YANG
(310) 917-1275
jyang@armagen.com
Research Institution:
n/a
Abstract
DESCRIPTION (provided by applicant): Civilian populations are at risk for exposure to chemical nerve gas agents such as organophosphates (OPs). These compounds affect both the peripheral nervous system (PNS) and the central nervous system (CNS). The CNS is affected because the OPs are lipid-soluble small molecules that easily penetrate the brain, owing to transport across the blood-brain barrier (BBB). Owing to the effects in the CNS, those individuals surviving exposure to chemical nerve gas agents are at risk for permanent brain damage. What is needed is a nerve gas antidote with the following characteristics: (a) ability to rapidly degrade the OP, such as an OP hydrolase; (b) ability to cross the human BBB, so that OPs in the CNS are inactivated; this will minimize the permanent brain damage in individuals that survive exposure to chemical nerve gas agents. The most active OP hydrolase in human blood is paraoxonase (PON)-1. However, PON-1 does not cross the BBB. The delivery of large molecule therapeutics, such as PON-1, across the human BBB is now possible with BBB fusion protein technology developed by the Company. The present research project will genetically engineer a novel PON-1 fusion protein, which will be a bi-functional molecule. The new fusion protein will both contain high PON-1 OP hydrolase activity and be able to cross the human BBB via receptor-mediated transport. This will be accomplished by fusing human PON-1 to a BBB molecular Trojan horse that carries attached drugs from blood into brain via transport across the BBB. The new fusion protein will be engineered so that both the BBB transport activity and the PON-1 OP hydrolase activity will be preserved. Civilian, and military, populations are at risk for exposure to chemical nerve gas agents such as organophosphates (OPs). These compounds affect both the peripheral nervous system (PNS) and the central nervous system (CNS). The CNS is affected because the OPs are lipid-soluble small molecules that easily penetrate the brain, owing to transport across the blood-brain barrier (BBB). The present work will genetically engineer a novel OP hydrolase fusion protein that is able to cross the BBB in humans by receptor-mediated transport.

* information listed above is at the time of submission.

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