Presentation by Dr. Nora Volkow of NIDA

Report
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:
 February 2012:
 Spring 2012:
 Spring/Summer 2012:
input from stakeholders
RFI published
Conduct virtual meetings
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 D3 ReceptorPreferring Ligand [11C]-PHNO in
Methamphetamine Polydrug Users
METH >Controls
METH users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain
(SN; +46%), globus pallidus (+9%) and ventral pallidum (+11%), and lower
binding in D2-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: 5HT1A receptor partial agonist)
Affinity
(Ki)
5HT1A
Partial Agonist
D1R
4-78 nM
>10 000
D2R
Partial Agonist
260nM
D3R
Antagonist
3.5 nM
D4R
Antagonist
78 nM
Buspirone Reduces Cocaine SelfAdministration In Rhesus Monkeys
J. Bergman, N. Mello, et al. submitted
Effects of Buspirone on [11C]PHNO (D3/D2R Ligand)
Binding in the Baboon Brain
0.060
putamendy1
GP dy1
CD dy1
CB dy1
putamendy2
GP dy2
CD dy2
0.050
Baseline
%ID/cc
0.040
0.030
0.020
0.010
0.000
With Buspirone
0.0
20.0
40.0
60.0
Time (min)
Buspirone (0.17mg/kg iv over 20 minutes) almost
completely blocked D3 receptors in the monkey brain
Kim et al., unpublished
80.0
Nicotine vaccines
•
•
Cocaine vaccines
NicVAX, failed to meet primary
endpoint in two phase III
studies
Higher abstinence was observed
in subjects with higher
immunity to nicotine.
Reduction in Cocaine Use in Vaccinated Patients
Strategies:
• novel carriers and/or adjuvants
for higher immunogenicity
• targeting subjects with robust
responses
• Combining with medications.
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 (11C-PE2i)
E1–E3–Ad5bgal
Fiber
Pre-vaccination
GNC cocaine analog
No cocaine
Penton base
Hexon
EDC, S-NHS crosslinker

Vaccinate with dAd5GNE
+ Cocaine
(1 MG/KG IV)
axial
coronal
sagittal
Post-vaccination
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
101
Non-immunized
100
0 3 5 7 9 12
Time post-administration (wk)
24
10-9 10-8
10-7
10-6
Cold cocaine competitor (mol/L)
Serum
Brain
100
Cocaine (ng/ml serum)
40
Cocaine (ng/g brain)
Kd = 6.7±1.5 nM
30
20
10
80
60
40
20
0
0
Non-immunized
AAVrh.10anti-Coc.Mab
Unbound
Total
serum
IgG
bound
Non-immunized
Unbound
Total
serum
IgG
bound
AAVrh.10antiCoc.Mab
100
80
Cocaine
Benzylecgonine
Norcocaine
Ecgonine methyl ester
Cocaethylene
60
40
20
Ambulatory count (cumulative, x 102)
102
100
90
80
70
60
50
40
30
20
10
0
% inhibition of serum
anti-cocaine antibody titer
103
AAVrh.10antiCoc.Mab
% inhibition
Serum anti-cocaine
antibody titer -1
105
104
Specificity
Affinity
0
0 10-6 10-5 10-4 10-3 10-2 10-1 100
Competitor concentration (mM)
Locomotor Activity
25
20
15
Non-immunized
+ cocaine
AAVrh.10antiCoc.Mab
+ cocaine
10
5
0
Non-immunized
+ PBS
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
Priming
condition:
Cocaine 10 mg/kg
(2 mg/kg)
Treatment = Single injection of either CocH vector
or control blank vector prior to extinction phase
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)
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
2010
Dr. Eric Verdin
Gladstone Institutes
New methods to detect and
model HIV latency
2009
Dr. Rafick-Pierre Sekaly
Vaccine & Gene Therapy
Institute, FL
Novel pathways for purging the
HIV reservoir
2011
Dr. David Ho
Aaron Diamond AIDS
Research Center
Develop a novel HIV therapy
that could be administered monthly
2008
Dr. Julio Montaner
University of British Columbia
HIV treatment as prevention in drug
using populations
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
NIDA’s Avant-Garde
Award Program
Is Now Open to
International Applicants
HAART as HIV Prevention
Decline in Community Viral Load is Strongly Associated
with Declining HIV Incidence among IDUs (ALIVE)
Montaner et al., Lancet 2008
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
Location TX Received
In 2010, An Estimated
Self Help Group
22.1 Million Americans
Outpatient Rehab
12 or Older Were Dependent On Inpatient Rehab
Any Illicit Drugs or Alcohol
Outpatient Mental
2.3
1.7
1.0
1.0
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
0.7
Doctor’s Office
0.7
Emergency Room
0.5
Prison or Jail 0.3
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%
82.2%
70.0%
60.0%
50.0%
40.0%
30.0%
20.0%
18.4%
10.0%
0.0%
American Journal of Public Health | April 19, 2012
On-site
testing
Off-site
testing
Screening and Brief Intervention in
Primary Health Care Settings
Mean Effect Size (% Decrease) in Illicit Substance Involvement
PERCENT
Pooled
Australia
Brazil
India
USA
30
25.3
23.6
25
20
18.3
19.7
16.7
15
10.9
11
10.3
10
8.5
5
0
2.3
Brief Intervention
Control
Hummeniuk R et al., Addition 2012; 107: 957-966.
Brain Imaging Studies of Microglial Activation
(PET and [11C](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
100%
Gardner, et al. CID 2011.
62%
40% 41%
19% 28%
328,475
24%
209,773
32%
426,590
36%
262,217
480,395
59%
349,622
0
Cohen, et al. MMWR 2011
437,028
200,000
80%
725,302
400,000
874,056
600,000
1,106,400
800,000
1,178,350
79%
655,542
1,000,000
941,950
1,200,000
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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