Presentation on theme: "Drug Abuse & Addiction Research:"— Presentation transcript:
1Drug Abuse & Addiction Research: Progress, Priorities, and Opportunities at NIDANational 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 AbuseNora D. Volkow, M.D.DirectorNational Institute on Drug AbuseNational Institutes of Health
2Strategy for Development of Scientific Strategic Plan for New SUD Institute Identify scientific and public health needs not addressedby NIHinput from NIH scientific staffinput from external stakeholders (researchers, advocates)Assess suggested scientific opportunities and public health needs, in light of missions of NIDA, NIAAA, NCI & other ICsDevelop a draft scientific strategic planIntegrate new scientific opportunities identified by NIH & the public with existing priorities in SUD researchSolicit public input on draft plan
3Scientific Strategic Plan Development Action Timeline June Fall 2012: input from stakeholdersFebruary 2012: RFI publishedSpring 2012: Conduct virtual meetingsSpring/Summer 2012: Conduct town hall meetings and teleconferences with stakeholdersFall 2012: Release of Draft Scientific Strategic Plan andpublic comment periodDecember 2012: Final Recommendations to NIH DirectorJanuary/February 2013: Include President’s FY 2014 BudgetBegin implementing Scientific Strategic Plan that is not dependent onreorganizationOctober 2013: National Institute of Substance Use andAddiction Disorders (NISUAD)
4Solicitation for Public Stakeholder Input Request for InformationFebruary 8, 2012Closing date: May 11, 2012How to Submit a Response : All comments must be submitted electronically to: d/add.cfmPublic MeetingsSchedule posted and updated on
5National Institute on Drug Abuse Portfolio FY 2011 ActualEpidemiology, Services & Prevention Research -- 23%Basic & Clinical Neuroscience & Behavioral Research %Pharmacotherapies & Medical Consequences -- 12%Intramural Research -- 8%Clinical Trials Network -- 5%RM&S -- 6%
6NIDA Priority Areas Prevention Research Treatment Interventions (Children & Adolescents)genetics/epigeneticsdevelopmentenvironmentco-morbidityTreatment Interventions(New Targets & New Strategies)Medical ConsequencesHIV/AIDS, HCVTeratogenic effects
7Big DATA Sets Allow Analysis of Complex Systems GeneticsEpigeneticsProteomicsBrain ImagingClinical DataSystems BiologyWith sequencing costs dropping dramatically, an explosion of very large sequencing datasets is at hand, which present challenges forhigh-level data analysis and for information technologyinfrastructure.Creighton Exp Rev Mol Diagn 2010
8Data and Informatics Working Group (DIWG) BIG DATA: Advisory Committee to NIH DirectorData and Informatics Working Group (DIWG)(Drs. Tabak and DeMets)MolecularProfilingGrantAdmin.ITManagementPhenotypingImagingThe first three subgroups will provide information to the DIWGon policies and investments needed to facilitate data sharing andintegration.The DIWG will develop recommendations to present to the ACDand 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.
9NIDA Priority Areas Prevention Research Treatment Interventions (Children & Adolescents)genetics/epigeneticsdevelopmentenvironmentco-morbidityTreatment Interventions(New Targets & New Strategies)Medical ConsequencesHIV/AIDS, HCVTeratogenic effects
10Methamphetamine Polydrug Users Higher Binding of the Dopamine D3 Receptor-Preferring Ligand [11C]-PHNO inMethamphetamine Polydrug UsersMETH >ControlsMETH 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
11Buspirone (D3 receptor antagonist +) Marketed as Buspar (Bristol Myers-Squibb 1980s) for anxietydisorders (proposed mechanism: 5HT1A receptor partial agonist)Affinity (Ki)5HT1APartial Agonist4-78 nMD1R>10 000D2R260nMD3RAntagonist3.5 nMD4R78 nMBuspirone Reduces Cocaine Self-Administration In Rhesus MonkeysJ. Bergman, N. Mello, et al. submitted
12Baseline With Buspirone Effects of Buspirone on [11C]PHNO (D3/D2R Ligand) Binding in the Baboon BrainBaselineWith BuspironeBuspirone (0.17mg/kg iv over 20 minutes) almost completely blocked D3 receptors in the monkey brainKim et al., unpublished
13Nicotine vaccines Cocaine vaccines NicVAX, failed to meet primary endpoint in two phase III studiesHigher abstinence was observed in subjects with higher immunity to nicotine.Strategies:novel carriers and/or adjuvants for higher immunogenicitytargeting subjects with robust responsesCombining with medications.Fahim et al., CNS Neurol Disord Drug TargetsCocaine vaccinesReduction in Cocaine Use in Vaccinated PatientsShen et al., , Clin Pharm & Ther 2012; 91(1):
14Nicotine Vaccine (dAd5GNE) Prevents Cocaine’s DAT Blockade in Brain PET imaging of DAT (11C-PE2i)E1–E3–Ad5bgalFiberPenton baseHexonNo cocaine+ Cocaine(1 MG/KG IV)Post-vaccinationPre-vaccinationaxialcaudateputamen(1MG/KG IV)coronalsagittalGNC cocaine analogEDC, S-NHS crosslinkerVaccinate with dAd5GNE10 wk latercocaine 1 mg/kg ivRon Crystal et al., 201214
15Monoclonal Antibodies Against Cocaine (AAVrh.10antiCoc.Mab) in Mice PersistenceSerum anti-cocaine antibody titer -1Time post-administration (wk)Non-immunizedAAVrh.10antiCoc.Mab10110010210310410524357912102030405060708090100Cold cocaine competitor (mol/L)% inhibitionAffinityKd = 6.7±1.5 nM10-910-710-810-6SpecificityCompetitor concentration (mM)% inhibition of serum anti-cocaine antibody titer20406080100CocaineBenzylecgonineNorcocaineEcgonine methyl esterCocaethylene10-110-210-310-410-510-6Locomotor Activity20406080100Non-immunizedAAVrh.10anti-Coc.MabCocaine (ng/ml serum)UnboundIgG boundTotal serumSerum10203040Cocaine (ng/g brain)AAVrh.10anti-Coc.MabNon-immunizedBrainAmbulatory count (cumulative, x 102)Time post-administration (min)1234567891011121314152025AAVrh.10antiCoc.Mab+ cocaineNon-immunized+ PBSRosenberg et al., Hum Gene Ther April 9.15
16Cocaine Hydrolase * P < .01 Encoded in Viral Vector Blocks the Reinstatement of Cocaine Seekingin Rats for 6 MonthsReinstatement Testingfollowing ExtinctionAdditional ReinstatementSessions# P < .01* P < .05* P < .01Primingcondition: Cocaine 10 mg/kg (2 mg/kg)Treatment = Single injection of either CocH vectoror control blank vector prior to extinction phaseAnker JJ et al., Biol Psychiatry 2011 Dec.
17NIDA Priority Areas Prevention Research Treatment Interventions (Children & Adolescents)genetics/epigeneticsdevelopmentenvironmentco-morbidityTreatment Interventions(New Targets & New Strategies)Medical ConsequencesHIV/AIDS, HCVTeratogenic effects
18International Applicants 2009Dr. Benjamin ChenMt. Sinai School of MedicineVisualizing early events of parenteral HIV transmission (cell-cell vs. free virus)2009Dr. Dana GabuzdaDana Farber Cancer Institute & Harvard Medical SchoolControl of T cell restoration in HIV-infected IV drug abusers2009Dr. Jonathan KarnCase Western Reserve UniversityDeveloping strategies for long-term HIV suppression2010Dr. Eric VerdinGladstone InstitutesNew methods to detect and model HIV latency2011Dr. David HoAaron Diamond AIDSResearch CenterDevelop a novel HIV therapythat could be administered monthly2009Dr. Rafick-Pierre SekalyVaccine & Gene Therapy Institute, FLNovel pathways for purging the HIV reservoir2008Dr. Ileana CristeaPrinceton UniversityQuantifying HIV –host interactome and regulation of gene expression2008Dr. Julio MontanerUniversity of British ColumbiaHIV treatment as prevention in drug using populationsNIDA’s Avant-GardeAward ProgramIs Now Open toInternational Applicants2008Dr. Jerome GroopmanBeth Israel Medical Center & Harvard Medical SchoolBlocking HIV transmission at the immune synapse
19HAART 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 VlahovMontaner et al., Lancet 2008
20IDU HIV+ Are Much Less Likely to Receive HAART Percentage Of Providers Who Would Defer ART By CD4+ Countand Injection Drug Use StatusWestergaard RP et al., J Int AIDS Soc 2012; 15:10.
21Opportunities with Health Care Reform to Expand Involvement of the Health Care Systemin Treatment of SUDLocation TX ReceivedIn 2010, An Estimated22.1 Million Americans12 or Older Were Dependent OnAny Illicit Drugs or AlcoholBut…Only 4.1 Million (19%)of These IndividualsHad Received Some Type ofTx In the Past Year and fewinvolved Health Care SystemsSelf Help GroupOutpatient RehabInpatient RehabOutpatient MentalHealth CenterHospital InpatientDoctor’s OfficeEmergency RoomPrison or Jail2.31.71.01.00.70.70.50.3Numbers in MillionsSource: 2010 NSDUH, National Findings, SAMHSA, OAS, 2011.
22Challenge: How to Integrate Drug Abuse & Addiction Screening, Prevention & Treatmentinto the Healthcare System
23Human Cortical Surface Area (406 twins) Hierarchical Genetic Organization ofHuman Cortical Surface Area (406 twins)Chen CH et al., Science 2012 March 30; 335( 6076):
24Implementation 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 AbusersHealth Care system (opportunities with Healthcare reform)Criminal Justice systemSubstance Abuse Treatment
25Implementing 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 testingOff-site testingCTN-0032American Journal of Public Health | April 19, 2012
26Screening and Brief Intervention in Primary Health Care Settings Mean Effect Size (% Decrease) in Illicit Substance InvolvementPERCENTBrief InterventionControlHummeniuk R et al., Addition 2012; 107:
27Brain Imaging Studies of Microglial Activation (PET and [11C](R)-PK11195)Sekine et al., J Neurosci (22):Microglia are activated in brains of METH abusersSIV Monkeys with encephalitis show microglia activationVenetti et al., J Clin Invest (7):981-9
28Ibudilast (cyclic AMP PDE inhibitor; anti-asthma drug) Antinflammatory effects (attenuate glial cell activation; inhibitschemokine 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 miceSnider et al., Eur J Neuroscience 2012