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Drug Abuse & Addiction Research:

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Presentation on theme: "Drug Abuse & Addiction Research:"— Presentation transcript:

1 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

2 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

3 Scientific Strategic Plan Development Action Timeline
June 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)

4 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: d/add.cfm Public Meetings Schedule posted and updated on

5 National Institute on Drug Abuse Portfolio
FY 2011 Actual Epidemiology, Services & Prevention Research -- 23% Basic & Clinical Neuroscience & Behavioral Research % Pharmacotherapies & Medical Consequences -- 12% Intramural Research -- 8% Clinical Trials Network -- 5% RM&S -- 6%

6 NIDA Priority Areas Prevention Research Treatment Interventions
(Children & Adolescents) genetics/epigenetics development environment co-morbidity Treatment Interventions (New Targets & New Strategies) Medical Consequences HIV/AIDS, HCV Teratogenic effects

7 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

8 Data and Informatics Working Group (DIWG)
BIG DATA: Advisory Committee to NIH Director Data and Informatics Working Group (DIWG) (Drs. Tabak and DeMets) Molecular Profiling Grant Admin. IT Management Phenotyping Imaging 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. The Advisory Committee to the Director (ACD) Data and Informatics Working Group (DIWG) will provide the ACD and the NIH Director with expert advice on the management, integration, and analysis of large biomedical datasets.

9 NIDA Priority Areas Prevention Research Treatment Interventions
(Children & Adolescents) genetics/epigenetics development environment co-morbidity Treatment Interventions (New Targets & New Strategies) Medical Consequences HIV/AIDS, HCV Teratogenic effects

10 Methamphetamine Polydrug Users
Higher Binding of the Dopamine D3 Receptor-Preferring 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

11 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 4-78 nM D1R >10 000 D2R 260nM D3R Antagonist 3.5 nM D4R 78 nM Buspirone Reduces Cocaine Self-Administration In Rhesus Monkeys J. Bergman, N. Mello, et al. submitted

12 Baseline With Buspirone
Effects of Buspirone on [11C]PHNO (D3/D2R Ligand) Binding in the Baboon Brain Baseline With Buspirone Buspirone (0.17mg/kg iv over 20 minutes) almost completely blocked D3 receptors in the monkey brain Kim et al., unpublished

13 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. 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 Cocaine vaccines Reduction in Cocaine Use in Vaccinated Patients Shen et al., , Clin Pharm & Ther 2012; 91(1):

14 Nicotine Vaccine (dAd5GNE) Prevents Cocaine’s DAT Blockade in Brain
PET imaging of DAT (11C-PE2i) E1–E3–Ad5bgal Fiber Penton base Hexon No cocaine + Cocaine (1 MG/KG IV) Post-vaccination Pre-vaccination axial caudate putamen (1MG/KG IV) coronal sagittal GNC cocaine analog EDC, S-NHS crosslinker Vaccinate with dAd5GNE 10 wk later cocaine 1 mg/kg iv Ron Crystal et al., 2012 14

15 Monoclonal Antibodies Against Cocaine (AAVrh.10antiCoc.Mab) in Mice
Persistence Serum anti-cocaine antibody titer -1 Time post-administration (wk) Non-immunized AAVrh.10antiCoc.Mab 101 100 102 103 104 105 24 3 5 7 9 12 10 20 30 40 50 60 70 80 90 100 Cold cocaine competitor (mol/L) % inhibition Affinity Kd = 6.7±1.5 nM 10-9 10-7 10-8 10-6 Specificity Competitor concentration (mM) % inhibition of serum anti-cocaine antibody titer 20 40 60 80 100 Cocaine Benzylecgonine Norcocaine Ecgonine methyl ester Cocaethylene 10-1 10-2 10-3 10-4 10-5 10-6 Locomotor Activity 20 40 60 80 100 Non-immunized AAVrh.10anti-Coc.Mab Cocaine (ng/ml serum) Unbound IgG bound Total serum Serum 10 20 30 40 Cocaine (ng/g brain) AAVrh.10anti-Coc.Mab Non-immunized Brain Ambulatory count (cumulative, x 102) Time post-administration (min) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 AAVrh.10antiCoc.Mab + cocaine Non-immunized + PBS Rosenberg et al., Hum Gene Ther April 9. 15

16 Cocaine Hydrolase * P < .01
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.

17 NIDA Priority Areas Prevention Research Treatment Interventions
(Children & Adolescents) genetics/epigenetics development environment co-morbidity Treatment Interventions (New Targets & New Strategies) Medical Consequences HIV/AIDS, HCV Teratogenic effects

18 International Applicants
2009 Dr. Benjamin Chen Mt. Sinai School of Medicine Visualizing early events of parenteral HIV transmission (cell-cell 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 long-term HIV suppression 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 2009 Dr. Rafick-Pierre Sekaly Vaccine & Gene Therapy Institute, FL Novel pathways for purging the HIV reservoir 2008 Dr. Ileana Cristea Princeton University Quantifying HIV –host interactome and regulation of gene expression 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 2008 Dr. Jerome Groopman Beth Israel Medical Center & Harvard Medical School Blocking HIV transmission at the immune synapse

19 HAART as HIV Prevention
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 Montaner et al., Lancet 2008

20 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.

21 Opportunities with Health Care Reform to
Expand Involvement of the Health Care System in Treatment of SUD Location TX Received In 2010, An Estimated 22.1 Million Americans 12 or Older Were Dependent On Any Illicit Drugs or Alcohol 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 Self Help Group Outpatient Rehab Inpatient Rehab Outpatient Mental Health Center Hospital Inpatient Doctor’s Office Emergency Room Prison or Jail 2.3 1.7 1.0 1.0 0.7 0.7 0.5 0.3 Numbers in Millions Source: 2010 NSDUH, National Findings, SAMHSA, OAS, 2011.

22 Challenge: How to Integrate Drug Abuse & Addiction
Screening, Prevention & Treatment into the Healthcare System

23 Human Cortical Surface Area (406 twins)
Hierarchical Genetic Organization of Human Cortical Surface Area (406 twins) Chen CH et al., Science 2012 March 30; 335( 6076):

24 Implementation of STTR in Substance Abusers
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 Health Care system (opportunities with Healthcare reform) Criminal Justice system Substance Abuse Treatment

25 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* On-site testing Off-site testing CTN-0032 American Journal of Public Health | April 19, 2012

26 Screening and Brief Intervention in Primary Health Care Settings
Mean Effect Size (% Decrease) in Illicit Substance Involvement PERCENT Brief Intervention Control Hummeniuk R et al., Addition 2012; 107:

27 Brain Imaging Studies of Microglial Activation
(PET and [11C](R)-PK11195) Sekine et al., J Neurosci (22): Microglia are activated in brains of METH abusers SIV Monkeys with encephalitis show microglia activation Venetti et al., J Clin Invest (7):981-9

28 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 Apr 8;6(4):e18633. Ibudilast attenuates methamphetamine locomotor activity and its sensitization in mice Snider et al., Eur J Neuroscience 2012

29 Major Gaps in the Implementation Cascade

30 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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