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Building(a(Research(Pipeline(at(NIH(

David(A.(Jett,(Ph.D.(

Program(Director(

NIH(Countermeasures(Against(Chemical(Threats(


NIH(Countermeasures(Against(Chemical(Threats((

(CounterACT)(

Better(Therapeutics(for(Treating(Chemical(Injury(

…(new(targets(

…(new(drugs(

…(reEpurposed(drugs(


Translational(Research(Pipeline(Funnel(

Target,ID,

Assay,Development,

Cost%$$%

Failure%Rate%

Screening,

Proof,of,Principle,

Optimization,&,

Preclinical,Efficacy,

IND>

Enabling,

Clinical,

FDA(

No(Good(Hits(

Bad(Chemistry(

Bad(Safety(Profile(


Windows(of(Opportunity(

Chemical((

Exposure(

Transport(to((

Hospital(

In(Hospital(

Home(

Pre>treatment, Pre>Hospital,Treatment, In>Hospital,and,Follow,,

Up,Treatment,

Safe,drugs,with,

no,side,effects,

Safe,drugs,that,work,fast,

Drugs,that,,can,prevent,,

long>term,effects,


DoseEResponse(

2X%LD50%

1X%LD50%

0.1X%LD50%

()$


100%%

Efficacy%(e.g.%Survival)%

0.1X%LD50%

0%

Chemical%

Insult%

2X%LD50%

1X%LD50%

5% 30% 60%

Time%of%Drug%Administration%(min)%


Small(Window(for(Some(


Outline(

I. Building(NIH(CounterACT:(Problems(&(Solutions(

II. Science(Advances(

III. Opportunities(for(Collaborating(with(ACMT(


Step(1:(Funding(


Pharmaceutical(Industry(

Lung cancer

Breast cancer

200,000

patients

Prostate cancer

Business%

model%

limitation%of%

traditional%

pharma%

Melanoma

ALS

NPC

6,000 diseases


Burden(of(Illness:(A(Case(for(Chemical(Poisons(

Chemical(Warfare(

• World(War(I(and(II:(thousands(of(fatalities(

• IranEIraq(War((1980E88):(thousands(of(fatalities(

• Current(conflicts(in(the(Middle(East:(unknown(

Terrorism/NonEmilitary(malicious(use(

• Tokyo(Subway(Attacks((1995):(thousands(affected;(13(fatalities(

• Jonestown(mass(suicide((1978):(900(fatalities(

• Tylenol(and(Excedrin(poisonings((1980’s):(few(fatalities(

Industrial(Accidents(

• Occur(Daily;(thousands(of(injuries(and(fatalities(annually(

• Bhopal(Union(Carbide(disaster((1984):(5,000(fatalities(

General(Poisonings(

• 4.2(million(calls(to(Poison(Control(Centers(in(2009(alone(


1,000%victims,%12%deaths%

Putamen))

and)thalamus)

Hippo)$

campus$

“…smaller)than)normal)regional)brain)volumes)in)the)insular)cortex)and)

neighboring)white)matter,)as)well)as)in)the)hippocampus)in)the)victims.)The)

reduced)regional)white)matter)volume)correlated)with)decreased)serum)

cholinesterase)levels)and)with)the)severity)of)chronic)somatic)complaints)related)

to)interoceptive)awareness)[anxiety].”)(p)


Step(2:(Find(the(Right(People(


Chemical)Classes)

e.g.,%

chlorine,%

phosgene%%%

e.g.,%sulfur%mustard,%

arsenicals%

Pulmonary

17%

Blistering

13%

Nerve

51%

e.g.,(nerve(“gas”,(

GABA(agents(

Cellular

19%

e.g.,%

cyanide%


The(Right(People(

• Nerve,agents,–,neurologists/neuroscientists,

• Pulmonary,agents,–,COPD,,Pulmonary,edema,

• Vesicants,–,burn,specialists,,wound,healing,

• Cellular,poisons,–,basic,researchers,


Chemical)“Toxidromes”)

Over(120(Chemicals(grouped(by(mechanism(and(toxicity(

1. Anticoagulants((e.g.(brodifacoum)(

2. Cellular(Respiration(Poisons((hydrogen(cyanide,(hydrogen(sulfide)(

3. Cholinergic(warfare((sarin,(soman)(

4. Cholinergic(pesticides((parathion,(aldicarb)(

5. Convulsant((picrotoxin,(TETS);((strychnine)(

6. Hemolytic/Metabolic((arsenic(trioxide,(thallium(sulfate)((arsine)(

7. Opioids((diacetyl(morphine)(

8. Lower(pulmonary((chlorine,(phosphine)(

9. Upper(pulmonary((ammonia,(sulfur(dioxide)((hydrogen(fluoride)(

10. Vesicants((sulfur(and(nitrogen(mustard)((phosgene(oxime)(


Step(3:(Incentivize(and(Empower(the(

Research(Community(to(Address(Mission(

Critical(Inadequacies…(

((=(Funding(+(People)(


CounterACT)Program)Snapshot)

NIH%

Target(ID(

((((((((Assay(

(((((Screening(

((((((Development%%

(((Proof(

(((of(

((((Principle(

Centers%of%Excellence%(U54)%and%Individual%Projects%(U01)%

DoD%Laboratories%(IAAs)%

Medicinal%Chemistry%

(proposed)%

Optimization/(

(((((((Preclinical((

(((((((Efficacy(

Efficacy%Research%

Facility%

(((((PreEIND/IDE(

((((((((((Studies(

Preclinical%

Contract%

Facility%

BARDA%

((((Clinical(

(((Trials(

Clinical%Trial%

Networks%

Industry%Partners%(SBIRs,%Subcontracts%to%Grants)%

Regulatory%Affairs%Consultative%Bureau%


The)Research)Network)

Harvard/MGH%

(Cyanide)%

UC%Davis%

(Nerve%Agents)%%

U%Colorado%

(Vesicants%SM,%

chlorine)%

Rutgers/UMDNJ%

(Vesicants%&%

Nerve%Agents)%

U.S.%Army%%

MRICD%

(Nerve%Agents)%

Centers of Excellence

Large Grants

Small Business

Small Grants

Contracts/IAAs


Step(4:(Partner(and(Leverage(Resources(


Other)Key)Partnerships)

National%

Toxicology%

Program%

(NIEHS)%

Unsolicited%

NIH%

Projects%

(All%NIH)%

NIH%

CounterACT%

CHEMM%

Tool%

(NLM)%

Anticonvulsant%

Screening%

Program%

(NINDS)%

Molecular%

Libraries%

(NIH%OD)%


Step(5:(Science(Excellence(


A(highEthroughput(

assay(for(anatoxin(

antidotes(

Molecular%

Libraries%

(NIH%OD)%


Doxycycline(facilitates(healing(of(mustard(exposed(eyes(

• Sections$of$whole$corneas$in$organ$culture$and$exposed$to$NM.$$$

• Epithelial)stromal$border$in$the$cornea,$the$epithelium$falls$off.$$

• Doxycycline$prevents$the$epithelium$from$falling$off!!$$


Catalytic$Antioxidant$

• SOD/catalase)like$

• Inhibits$Lipid$Peroxidation$

• Scavenges$Peroxynitrite$

• !rats!were!exposed!to!500!ppm!chlorine!gas!for!30!minutes.!!

• Forty;five! minutes! following! chlorine! exposure! AEOL! 10150! was!

injected!subcutaneously!(sc)!at!!5!mg/kg!and!then!every!4!hours!for!

24! hours! and! then! once! daily,! or! no! treatment! (NT),! or! equal!

volume!of!PBS.!


A)

Control)

*)

*

0.5 mm

B

CEES)7.5%)

0.5 mm


Nitrocobinamide:(Cyanide(antidote(


Organophosphorus%(OP)%pesticides%and%chemical%weapons%


SeizureEPathology(Model(

PHYSIOLOGICAL%

AND%METABOLIC%

EFFECTS%

NERVE%

AGENT%

INHIBITION%

OF%AChE%

RISE%IN%

ACh%

ACTIVATION%OF%

MUSCARINIC%

RECEPTORS%

EPILEPTIFORM%

ACTIVITY%

NEURONAL%

DAMAGE%

Therapeutic%Approaches:%

• %%Anticholinergics%

• %%AChE%Reactivators%

• %%Anticonvulsants%

• %%Neuroprotectants%

• %%Single%Antidote%

ACTIVATION%OF%

GLUTAMATE%

RECEPTORS%

INTRACELLULAR%

ACCUMULATION%

OF%Ca++%


Anticonvulsant(Screening(

Anticonvulsant%

Screening%

Program%

(ASP)%

A(

S(

P(

In)Vivo)

Screens)

In)Vitro)

Screens)

Validated In Vivo

Models

A(

R(

M(

Y(

Institute(of(Chemical(Defense(

BATTELLE(


GluK1/AMPA(Receptor(Antagonist(LY293558(Stops(Seizures(and(Protects(Neurons,(

without(Pretreatment(

IM$given$@$20$min;$$

24hr$period$after$soman.)

IM$given$@$20$min;$7$days$after$soman$


NRG;1!Prevents!CNS!Neuronal!Injury!following!OP!Exposure!using!

Fluorojade!B!Labeling!

Li)et)al.)2012.)Toxicol)Appl)

Pharmacol.)262(2):194R204.)


Midazolam)Clinical)Trial)


Midazolam(Trial(Details(

Hypothesis:(IM(midazolam(is(as(

effective(as(IV(lorazepam(at(stopping(

convulsions(prior(to(ED(arrival.(

Method:(Double(blinded,(Double(

Dummy;(4,314(paramedics,(79(

hospitals.(1,023(enrolled.(

Conclusion:(Intramuscular(

midazolam(is(the(optimal(initial(

prehospital(treatment(for(status(

epilepticus(by(paramedics(

Accompanying editorial: “…the findings in this

study should lead to a systematic change in the way

patients in status epilepticus are treated en route to

the hospital.” −Lawrence Hirsch


Final(Step:(Showcase(Results(

and(Impact(on(Science(

Go(to(ACMT!(


CounterACT(has(now(engaged(some(of(the(best(scientists(in(the(world,(and(is(

responsible(for(a(huge(improvement(in(the(quality(of(publications(in(the(area(of(

therapeutics(for(toxic(chemicals((Over(475(Publications).((


And(CounterACT(research(can(have(broad(implications(

Basic)

Proof)of)

Principle)

Preclinical)

Clinical)and)

Diagnostic)

New)screening)

tools)for)neuroR

active)drugs)

New)therapies)for)

SE)and)neuropathic)

pain)

Delivery)of)drugs)

across)the)bloodR

brain)barrier)

Development)of)

advanced)

platform)

technologies)

Structural)

biology)of)

neuronal)

receptors)

Advances)in)

protein)

engineering)

Neuroprotectants)

for)

neurodegenerative)

disease)and)stroke)

Technologies)to)

improve)

pharmacokinetics)

of))drugs)

Portable)devices)

such)as)EEG)to)

detect)nonR

convulsive)

seizures)

from)Jett)DA)2010.)Science)Trans)Med)2(23):23ps12))


Funding(Opportunities(

For(Details(Go(To(

www.ninds.nih.gov/counteract(


Soliciting(Cooperative(Agreement(Grant(Applications(

• Research(Centers(of(Excellence((U54)(

• Research(Projects((U01)(

• Small(Grants((R21)(

• SBIR(Grants((R43/44)(


No(Cost(Contract(Services(–(Seeking(PreEproposals(

Preclinical(ADMET(&(Manufacturing(

Pilot(studies(to(GLP(INDEenabling(

Efficacy(Studies(

Pilot(studies(to(Pivitol(studies(

Other(

Assay(Development((PARE12E058)(

Med(School(Loan(Repayment(!!!((call(me)(


Drs.)Ernie)Takafuji)

and)Gen)Platoff)

Dr.)Randy)Stewart

NINDS*

NIAID

NIEHS*

Drs.)Sri)Nadadur)and)

Elizabeth)Maull

Dr.)Houmam))Araj

NEI*

NIAMS*

Dr.)Hung)Tseng

Dr.)Bert)

Hakkinen

NLM

NIGMS

NICHD

Dr.)David)Siegel

Dr.)Richard)

Okita

*$ICs)with)active)grants$


CounterACT(Central(Office(at(NINDS(

Dr.)David)Yeung,)Program)Manager)

Dr.)Margaret)Ochocinska,)Program)Analyst)

Wendy)Vasquez,)Program)Coordinator)

Jonlethia)King,)Program)Assistant)

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