Stem Cell Study of Genetics and Drug Addiction
Condition: Induced Pluripotent Stem Cells
Study type: Observational

Summary: 
      Background:

      - Researchers are interested in studying the roles that genes play in drug and alcohol
      addiction. Genes seem to account for about half of the differences between people who become
      addicted to drugs and people who do not. This study will collect blood and skin cell samples.
      These cells will be used to develop stem cells that are useful for studying how genes are
      related to drug use and dependence.

      Objectives:

      - To study genetic and cellular differences between people who are addicted to drugs and
      those who are not.

      Eligibility:

        -  Individuals between 21 and 65 years of age who do not use drugs.

        -  Individuals between 21 and 65 years of age who are in treatment with buprenorphine or
           methadone.

      Design:

        -  Participants will be screened with a brief physical exam and medical history.

        -  Participants will also answer questions about physical and mental health, quality of
           life, and history of drug and alcohol use. A urine sample and cheek swab sample will be
           collected.

        -  Participants whose genetic samples match the study requirements will be asked to come
           back to provide a skin biopsy sample and a second urine sample.
    

Detailed description: 
      Background - The molecular- and cellular-based mechanisms that contribute to the initiation
      and development of addiction remain to be elucidated. Estimates have suggested that 40-60
      percent of the vulnerability to addiction may be attributable to genetic aberrations.
      Multiple chromosomal regions have been linked to addiction including those containing the
      dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) genes. Current efforts
      to understand how polymorphisms in these monoamine transporters contribute to the molecular
      mechanisms of addiction are severely hindered by the inability to directly interrogate neural
      cell types from the patients. There is great potential for patient-specific iPS cell
      technology to profoundly impact our understanding of human development and disease by
      providing genetically distinct, functional sources of human cells.

      Objective - The objective of the research is to develop a cell-based system whereby neural
      cells from afflicted individuals can be functionally assayed to interrogate the molecular
      mechanisms underlying addiction.

      Study population Controls (non-drug users) and opioid dependent adults receiving opioid
      agonist therapy aged 21- 65 will be enrolled.

      Design Participants demographic characteristics, psychosocial evaluation, and psychiatric,
      medical, and drug use histories will be characterized. DNA will be collected via cheek swabs
      of up to 30 potential participants for determination of dopamine transporter (DAT) and
      vesicular monoamine transporter (VMAT2) gene polymorphisms. Participants (N=16) with suitable
      polymorphisms will be asked to under go skin biopsies; 2 individuals for each of two
      genotypes for each gene (DAT or VMAT), i.e., 8 samples from addicts and 8 samples for control
      subjects. Collaborators at Case Western Reserve University will use the skin cells to derive
      and characterize patient-specific, induced pluripotent stem (iPS) cells that carry monoamine
      transporter polymorphisms for the hDAT1 and hVMAT2 genes. They will differentiate
      patient-specific iPS cells line into dopaminergic neurons and carry out a detailed and
      functional characterization of these cells to identify their molecular characteristics.

      Outcome measures - Biological specimens from the addiction patients and controls will be used
      to derive and characterize patient-specific, induced pluripotent stem (iPS) cells that carry
      monoamine transporter polymorphisms. Patient-specific iPS cells lines will be differentiated
      into dopaminergic neurons. In follow up studies, we will characterize, compare, and
      functionally assay these patient-specific, iPS cell-derived dopaminergic neurons from control
      and addiction patients that carry polymorphisms for hDAT1 and hVMAT2 gene to investigate any
      possible association with dopamine neurotransmission variations and vulnerability to
      addiction.
    

Time perspective: Prospective
Keywords: Induced Pluripotent Stem Cell (iPS) Cell Lines; Addiction; Addiction-Associated Human Gene Variants; Dopamine Transporter