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Center of Catalytic Bioscanvenger Medical Defense Research II: Discovery, Formula

Award Number: U54NS058183
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Center of Catalytic Bioscanvenger Medical Defense Research II: Discovery, Formula - DESCRIPTION (provided by applicant): Organophosphorus (OP) compounds, including both nerve agents and pesticides, represent a serious potential threat to the health of the civilian population. Because they are relatively easy to synthesize, are extremely toxic, and may be difficult to rapidly diagnose or treat in a mass casualty situation, they are considered to be a likely tool for use by terrorists in civilian settings. The CounterACT solicitation identifies a need for a rapid, post-exposure protection that can be easily administered to civilians in a mass casualty scenario. We intent to fulfill this requirement by developing a drug formulation that is amenable to use in an autoinjector, can be delivered via intramuscular injection, will become rapidly bioavailable, will have a sufficient long in vivo residence to protect against slowly metabolized OP compounds, and will have sufficient catalytic efficiency and broad spectrum reactivity to protect against a variety of OP threats. The overarching goal of this U54 Center renewal effort, the "Center for Catalytic Bioscavenger Medical Defense Research II: Discovery, Formulation and Preclinical Evaluation", is to define, characterize, and transition to the NIH for advanced development a drug formulation that will afford post-exposure protection to victims of OP poisoning. The path we will utilize to accomplish this goal has three major initiatives that will be performed in parallel; the vision for this approach is that at the end of year three all of the concurrent efforts will combine to identify a single best candidate drug which will then become the Center's focus for the remaining two years. The first initiative that the Center will pursue is the generation through rationale design, directed evolution, and high throughput library screening of enzyme variants based on OPH (from fi. diminuta) and/or on a recombinant, bacterially expressible paraoxonase 1 (P0N1). Variants will be screened for broad spectrum activity against multiple OP pesticides and nerve agents. They will also be designed to possess high catalytic efficiency, which will allow for the rapid detoxification of OPs in the blood of exposed individuals. These efforts will identify a single "best variant" or cocktail of variants that meet the disparate requirements for high catalytic activity and broad spectrum reactivity. The second major initiative of the Center will be the characterization of different encapsulation and formulation approaches that will stabilize enzyme activity in vitro (to promote economical long term storage), will allow rapid (>5 minutes) bioavailability in circulation after an intramuscular injection (to be consistent with the intended use in a mass casualty situation), and to result in long (>48 hour) circulatory stability, ensuring that protection is afforded against both rapid onset OPs like the G agents, slow onset OPs like VX and VR, and pesticides that require in vivo metabolism to be converted into their more toxic forms; to afford protection against different OP compounds with very disparate distribution profiles, we will require both rapid bioavailability and long-lived circulatory stability. The third major initiative will be a determination of the utility of co- administration of conventional therapeutic drugs (atropine, an oxime, and/or an anti-convulsant) as an adjunct that will enhance the therapeutic efficacy of a catalytic scavenger. One of the only published reports detailing the use of a catalytic bioscavenger to provide protection against an OP also included an experiment where atropine and the oxime 2-PAM were co-administered with an enzyme; the amount of protection afforded was substantially greater than was predicted based on the efficacy of either drug therapy alone, suggesting that the use of conventional therapeutic drugs with a catalytic scavenger may result in a synergistic rather than additive level of protection.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = -$2,319,318 )
2018	2013	ARMY, UNITED STATES DEPARTMENT OF THE	E2900 RICKETTS POINT RD	ABERDEEN PROVING GROUND	MD	21010	HARFORD	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	9/30/2018	SUPPLEMENT FOR EXPANSION	-$2,319,318
														Subtotal = -$2,319,318

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2013	US ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE	3100 RICKETTS POINT ROAD	ABERDEEN PROVING GROUND	MD	21010	HARFORD	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	11/16/2015	NON-COMPETING CONTINUATION	-$2,364,933
2016	2013	US ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE	3100 RICKETTS POINT ROAD	ABERDEEN PROVING GROUND	MD	21010	HARFORD	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	11/18/2015	NON-COMPETING CONTINUATION	$2,364,933
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $2,464,184 )
2013	2013	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	5/27/2013	SUPPLEMENT FOR EXPANSION	$99,251
2013	2013	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	8	9/13/2013	NON-COMPETING CONTINUATION	$2,364,933
2013	2012	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	5/1/2013	NON-COMPETING CONTINUATION	$0
2013	2012	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	3/4/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,464,184

Issue Date FY: 2012 ( Subtotal = $2,435,232 )
2012	2012	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	7	9/26/2012	NON-COMPETING CONTINUATION	$2,435,232
2012	2011	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	5/18/2012	COMPETING CONTINUATION	$0
2012	2011	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	4/26/2012	COMPETING CONTINUATION	$0
2012	2011	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	6	8/23/2012	COMPETING CONTINUATION	$0
2012	2011	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	10/31/2011	COMPETING CONTINUATION	$0
2012	2010	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	5/21/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,435,232

Issue Date FY: 2011 ( Subtotal = $2,650,595 )
2011	2011	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	9/23/2011	COMPETING CONTINUATION	$2,650,595
2011	2011	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	10/31/2011	COMPETING CONTINUATION	$0
2011	2010	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	9/23/2011	NON-COMPETING CONTINUATION	$0
2011	2010	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/24/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,650,595

Issue Date FY: 2010 ( Subtotal = $2,206,282 )
2010	2010	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	8/2/2010	NON-COMPETING CONTINUATION	-$735,427
2010	2010	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	7/22/2010	NON-COMPETING CONTINUATION	$2,941,709
2010	2009	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/16/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,206,282

Issue Date FY: 2009 ( Subtotal = $2,128,030 )
2009	2009	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/20/2009	NON-COMPETING CONTINUATION	$2,128,030
2009	2008	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/3/2008	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,128,030

Issue Date FY: 2008 ( Subtotal = $2,830,710 )
2008	2008	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	9/26/2008	SUPPLEMENT FOR EXPANSION	$50,000
2008	2008	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/18/2008	NON-COMPETING CONTINUATION	$2,780,710
														Subtotal = $2,830,710

Issue Date FY: 2007 ( Subtotal = $2,805,523 )
2007	2007	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/21/2007	NON-COMPETING CONTINUATION	$2,805,523
														Subtotal = $2,805,523

Issue Date FY: 2006 ( Subtotal = $2,810,050 )
2006	2006	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/30/2006	NEW	$2,810,050
														Subtotal = $2,810,050

Grand Total All Awards = $18,011,288

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Center of Catalytic Bioscanvenger Medical Defense Research II: Discovery, Formula

Award Number: U54NS058183

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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