Presentation by Dr. Nora Volkow of NIDA

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Drug Abuse & Addiction Research:

Progress, Priorities, and Opportunities at NIDA

National Institute on Drug Abuse

Bringing the full power of science to bear on drug abuse and addiction

Nora D. Volkow, M.D.

Director

National Institute on Drug Abuse

Nora D. Volkow, M.D.

Director

National Institute on Drug Abuse

National Institutes of Health

Strategy for Development of Scientific

Strategic Plan for New SUD Institute

Identify scientific and public health needs not addressed by NIH

• input from NIH scientific staff

• input from external stakeholders (researchers, advocates)

Assess suggested scientific opportunities and public health needs, in light of missions of NIDA, NIAAA, NCI & other ICs

Develop a draft scientific strategic plan

Integrate new scientific opportunities identified by NIH & the public with existing priorities in SUD research

Solicit public input on draft plan

Scientific Strategic Plan Development

Action Timeline

June 2011 - Fall 2012: input from stakeholders

February 2012: RFI published

Spring 2012: Conduct virtual meetings

Spring/Summer 2012: Conduct town hall meetings and teleconferences with stakeholders

Fall 2012: Release of Draft Scientific Strategic Plan and public comment period

December 2012: Final Recommendations to NIH Director

 January/February 2013: Include President’s FY 2014 Budget

Begin implementing Scientific Strategic Plan that is not dependent on reorganization

October 2013: National Institute of Substance Use and

Addiction Disorders (NISUAD)

Solicitation for Public Stakeholder Input

Request for Information

February 8, 2012

Closing date: May 11, 2012

How to Submit a Response : All comments must be submitted electronically to: http://grants.nih.gov/grants/guide/rfi_files/nih_nisua d/add.cfm

Public Meetings

Schedule posted and updated on http://feedback.nih.gov/index.php/category/suaa/

National Institute on Drug Abuse Portfolio

FY 2011 Actual

Basic & Clinical Neuroscience &

Behavioral Research -- 45%

Epidemiology, Services &

Prevention Research -- 23%

Pharmacotherapies & Medical

Consequences -- 12%

Clinical Trials Network -- 5%

Intramural Research -- 8%

RM&S -- 6%

NIDA Priority Areas

Prevention Research

(Children & Adolescents) genetics/epigenetics development environment co-morbidity

Treatment Interventions

(New Targets & New Strategies )

Medical Consequences

HIV/AIDS, HCV

Teratogenic effects

Big DATA Sets

Allow Analysis of Complex Systems

Genetics

Epigenetics

Proteomics

Brain Imaging

Clinical Data

Systems Biology

With sequencing costs dropping dramatically, an explosion of very large sequencing datasets is at hand, which present challenges for high-level data analysis and for information technology infrastructure.

Creighton Exp Rev Mol Diagn 2010

BIG DATA: Advisory Committee to NIH Director

Data and Informatics Working Group (DIWG)

(Drs. Tabak and DeMets)

Molecular

Profiling

Phenotyping Imaging

Grant

Admin.

IT

Management

The first three subgroups will provide information to the DIWG on policies and investments needed to facilitate data sharing and integration.

The DIWG will develop recommendations to present to the ACD and the NIH Director on policies regarding the management, integration and analysis of research data and administrative data.

NIDA Priority Areas

Prevention Research

(Children & Adolescents) genetics/epigenetics development environment co-morbidity

Treatment Interventions

(New Targets & New Strategies )

Medical Consequences

HIV/AIDS, HCV

Teratogenic effects

Higher Binding of the Dopamine D

3

Receptor-

Preferring Ligand [ 11 C]-PHNO in

Methamphetamine Polydrug Users

METH >Controls

METH users had higher [ 11 C]-(+)-PHNO binding in the D

3

-rich midbrain

(SN; +46%), globus pallidus (+9%) and ventral pallidum (+11%), and lower binding in D

2

-rich dorsal striatum (−4% to −12%)

Boileau et al., J Neurosci. 2012

Buspirone (D3 receptor antagonist +)

Marketed as Buspar (Bristol Myers-Squibb 1980s) for anxiety disorders (proposed mechanism: 5HT

1A receptor partial agonist)

Affinity

(Ki)

5HT1A Partial Agonist 4-78 nM

D1R

D2R

D3R

D4R

Partial Agonist

Antagonist

Antagonist

>10 000

260nM

3.5 nM

78 nM

Buspirone Reduces Cocaine Self-

Administration In Rhesus Monkeys

J. Bergman, N. Mello, et al. submitted

Effects of Buspirone on [

11

C]PHNO (D3/D2R Ligand)

Binding in the Baboon Brain

Baseline

With Buspirone

0,060

0,050

0,040

0,030

0,020

0,010

0,000

0,0 putamendy1

GP dy1

CD dy1

CB dy1 putamendy2

GP dy2

CD dy2

20,0 40,0 60,0

Time (min)

80,0

Buspirone (0.17mg/kg iv over 20 minutes) almost completely blocked D3 receptors in the monkey brain

Kim et al., unpublished

Nicotine vaccines

NicVAX, failed to meet primary endpoint in two phase III studies

Higher abstinence was observed in subjects with higher immunity to nicotine.

Cocaine vaccines

Strategies:

• novel carriers and/or adjuvants for higher immunogenicity

• targeting subjects with robust responses

Combining with medications.

Reduction in Cocaine Use in Vaccinated Patients

Fahim et al., CNS Neurol Disord Drug Targets. 2011.

Shen et al., , Clin Pharm & Ther 2012; 91(1): 60-70.

Nicotine Vaccine (dAd5GNE) Prevents Cocaine’s

DAT Blockade in Brain

PET imaging of DAT ( 11 C-PE2i)

Pre-vaccination

E1

E3

Ad5bgal

Fiber

Penton base

GNC cocaine analog

Hexon

EDC, S-NHS crosslinker

 Vaccinate with dAd5GNE

No cocaine

+ Cocaine

(1 MG/KG IV) axial coronal

Post-vaccination sagittal caudate

No cocaine putamen

10 wk later cocaine 1 mg/kg iv

Ron Crystal et al., 2012

+ Cocaine

(1MG/KG IV)

Monoclonal Antibodies Against Cocaine

(AAVrh.10antiCoc.Mab) in Mice

Persistence

10 5

10 4

10 3

10 2

10 1

10 0

AAVrh.10antiCoc.Mab

Non-immunized

0 3 5 7 9 12

Time post-administration (wk)

24

Affinity

100

90

80

70

60

50

40

30

20

10

0

K d

= 6.7

± 1.5 nM

10 -9 10 -8 10 -7 10 -6

Cold cocaine competitor (mol/L)

Specificity

100

80

60

40

20

0

0 10 -6 10 -5 10 -4 10 -3 10 -2 10 -1

Competitor concentration (mM)

10 0

Cocaine

Benzylecgonine

Norcocaine

Ecgonine methyl ester

Cocaethylene

40

30

20

10

0

Brain

Serum

100

80

60

40

20

Non-immunized AAVrh.10anti-Coc.Mab

0

Unbound Total

IgG bound serum

Non-immunized

Unbound Total

IgG bound serum

AAVrh.10anti-

Coc.Mab

Locomotor Activity

25

20

Non-immunized

+ cocaine

15

10

AAVrh.10antiCoc.Mab

+ cocaine

5

Non-immunized

+ PBS

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Time post-administration (min)

Rosenberg et al., Hum Gene Ther. 2012 April 9.

Cocaine Hydrolase

Encoded in Viral Vector Blocks the Reinstatement of Cocaine Seeking in Rats for 6 Months

Reinstatement Testing following Extinction

Additional Reinstatement

Sessions

#

P < .01

*

P < .05

*

P < .01

Treatment = Single injection of either CocH vector or control blank vector prior to extinction phase

Priming condition: Cocaine 10 mg/kg (2 mg/kg)

Anker JJ et al., Biol Psychiatry 2011 Dec.

NIDA Priority Areas

Prevention Research

(Children & Adolescents) genetics/epigenetics development environment co-morbidity

Treatment Interventions

(New Targets & New Strategies )

Medical Consequences

HIV/AIDS, HCV

Teratogenic effects

2009

Dr. Benjamin Chen

Mt. Sinai School of Medicine

Visualizing early events of parenteral HIV transmission (cellcell vs. free virus)

2010

Dr. Eric Verdin

Gladstone Institutes

New methods to detect and model HIV latency

2011

Dr. David Ho

Aaron Diamond AIDS

Research Center

Develop a novel HIV therapy that could be administered monthly

2008

Dr. Ileana Cristea

Princeton University

Quantifying HIV –host interactome and regulation of gene expression

2008

Dr. Jerome Groopman

Beth Israel Medical Center &

Harvard Medical School

Blocking HIV transmission at the immune synapse

2009

Dr. Dana Gabuzda

Dana Farber Cancer Institute &

Harvard Medical School

Control of T cell restoration in

HIV-infected IV drug abusers

2009

Dr. Jonathan Karn

Case Western Reserve University

Developing strategies for longterm HIV suppression

2009

Dr. Rafick-Pierre Sekaly

Vaccine & Gene Therapy

Institute, FL

Novel pathways for purging the

HIV reservoir

2008

Dr. Julio Montaner

University of British Columbia

HIV treatment as prevention in drug using populations

NIDA ’ s Avant-Garde

Award Program

Is Now Open to

International Applicants

HAART as HIV Prevention

Montaner et al., Lancet 2008

Decline in Community Viral Load is Strongly Associated with Declining HIV Incidence among IDUs (ALIVE)

GD Kirk, N Galai1, J Astemborski, B Linas, D Celentano, SH Mehta, D Vlahov

IDU HIV+ Are Much Less Likely to Receive HAART

Percentage Of Providers Who Would Defer ART By CD4+ Count and Injection Drug Use Status

Westergaard RP et al., J Int AIDS Soc 2012; 15:10.

Opportunities with Health Care Reform to

Expand Involvement of the Health Care System in Treatment of SUD

In 2010, An Estimated

22.1 Million Americans

12 or Older Were Dependent On

Outpatient Rehab

Inpatient Rehab

Any Illicit Drugs or Alcohol

Self Help Group

Outpatient Mental

Health Center

But…Only 4.1 Million (19%) of These Individuals

Had Received Some Type of

Tx In the Past Year and few involved Health Care Systems

Hospital Inpatient

Doctor ’ s Office

Emergency Room

Prison or Jail

Location TX Received

0.3

0.5

0.7

0.7

1.0

1.0

1.7

2.3

0 .5 1.0 1.5 2.0 2.5

Numbers in Millions

Source: 2010 NSDUH, National Findings, SAMHSA, OAS, 2011.

Challenge: How to Integrate Drug Abuse & Addiction

Screening, Prevention & Treatment into the Healthcare System

Hierarchical Genetic Organization of

Human Cortical Surface Area (406 twins)

Chen CH et al., Science 2012 March 30; 335( 6076): 1634-1636.

Despite increases in ART incidence of HIV in USA has remained stable at ∼ 56,300 new infections per year. This is likely to reflect in part failure to treat those with SUD .

Of the 1.1 M individuals living with HIV in the US, 21% are estimated to be unaware of their HIV infection.

Undetected cases are likely to be higher among individuals with SUD.

Implementation of STTR in Substance Abusers

1. Health Care system (opportunities with Healthcare reform)

2. Criminal Justice system

3. Substance Abuse Treatment

Implementing Rapid HIV Testing With or Without

Counseling in Drug Tx Centers

Combined on-site rapid testing participants received more HIV results

( 82.2% ) than off-site testing referral participants ( 18.4% )

• p < 0.001, aRR 4.52,

97.5% CI (3.57, 5.72)

* No effect of counseling*

90,0%

80,0%

70,0%

60,0%

50,0%

40,0%

30,0%

20,0%

10,0%

0,0%

82,2%

On-site testing

18,4%

Off-site testing

American Journal of Public Health | April 19, 2012

Screening and Brief Intervention in

Primary Health Care Settings

Mean Effect Size (% Decrease) in Illicit Substance Involvement

Pooled Australia Brazil India USA

30

25

25,3

23,6

19,7

20

18,3

16,7

15

10,9 11

10 8,5

10,3

5

0

Brief Intervention

2,3

Control

Hummeniuk R et al., Addition 2012; 107: 957-966.

Brain Imaging Studies of Microglial Activation

(PET and [

11

C](R)-PK11195)

Microglia are activated in brains of METH abusers

Sekine et al., J Neurosci. 2008 28(22):5756-61

SIV Monkeys with encephalitis show microglia activation

Venetti et al., J Clin Invest. 2004 113(7):981-9

Ibudilast (cyclic AMP PDE inhibitor; anti-asthma drug)

Antinflammatory effects (attenuate glial cell activation; inhibits chemokine production; increases IL-10 production)

Clinical trials testing it in MS, opioid withdrawal, and neuropathic pain.

Prevents HIV-1 Tat-mediated activation of microglial cells (tx HAND)

Kiebala et al., PLoS One. 2011 Apr 8;6(4):e18633.

Ibudilast attenuates methamphetamine locomotor activity and its sensitization in mice

Snider et al., Eur J Neuroscience 2012

Major Gaps in the Implementation Cascade

1 400 000

1 200 000

1 000 000

800 000

600 000

400 000

200 000

0

100%

79%

80%

59%

62%

40%

41%

32%

Gardner, et al. CID 2011.

Cohen, et al. MMWR 2011

24%

36%

19%

28%

HPTN 052

Early ART prevented linked transmission of HIV

Unlinked transmissions were noted despite intensive couples counseling

Early ART reduced the number of clinical events observed

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