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GENE THERAPY

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GENE THERAPY By Sam Lai and Meng Lee Gene Therapy Introduction : What is it? Gene Therapy : A Closer Look How much did you learn?! Case Study : SCID Model for Gene ... – PowerPoint PPT presentation

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Title: GENE THERAPY


1
GENE THERAPY
  • By Sam Lai and Meng Lee

2
Gene Therapy
  • Introduction What is it?
  • Gene Therapy A Closer Look
  • How much did you learn?!
  • Case Study SCID
  • Model for Gene Therapy Medical Framework
  • Discussion / QA

3
What is it?
  • Gene therapy, which was first conceived in the
    mid-1970s, aims to insert working copies of genes
    into cells containing dysfunctional ones
  • treat, cure, or ultimately prevent disease by
    changing the expression of a person's genes
  • current gene therapy is primarily experimental,
    with most human clinical trials only in the
    research stages
  • Most often in context of treating lethal and
    disabling diseases, potential also for disease
    prevention

4
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5
Human Genome Project
  • A genome is all the DNA in an organism, including
    its genes. Genes carry information for making all
    the proteins required by all organisms
  • Variations in structure of persons genes
    collectively helps define us as individuals
  • Rationale for GT is based on knowledge of the
    human genetic code
  • Began formally in 1990, set as a 13 year project.

6
HGP GOALS
  • Identify aproximately 30,000 genes
  • Determine 3 billion chemical base pairs that make
    up human DNA
  • Store information in databases
  • Improve tools for data analysis
  • Address ethical, legal and social issues that
    might arise from this

7
HGP cont
  • Achieve these goals, researchers look at genetic
    makeup of other organisms
  • This project is important because the
    government's dedication to the transfer of
    technology to the private sector

8
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9
Which Cells Targeted?
  • somatic gene therapy the recipient's genome is
    changed, but the change is not passed along to
    the next generation
  • germline gene therapy, the sex cells are changed
    with the goal of passing these changes to their
    offspring. But, this is not being actively
    investigated, at least not humans, although a lot
    of discussion is being conducted about its value
    and desirability.

10
Somatic Stem Cells
  • Somatic stem cells are remarkable cells in the
    body
  • These different stem cell types are targets for
    gene therapy
  • Genetically treated stem cells, when reintroduced
    into the patient's body are expected to naturally
    travel through the blood stream to the bone
    marrow.

11
Germline Gene Therapy
  • Gene therapy in germline cells has the potential
    to affect not only the individual, but also their
    children as well.
  • Any genetic changes in the reproductive cells or
    changes made to the embryo before the stage of
    differentiation, would affect all future
    offspring of that person. This makes an vital
    distinction, affecting major ethcial issues

12
Delivery of Genes
  • Need an efficient method to deliver the gene to
    live cells.
  • Done via vectors (gene carriers), delivering
    therapeutic genes to cells - common vector is
    viruses
  • Alternative delivery methods seen with use of
    lipids and proteins

13
Use of Viruses
  • Viruses evolved a way of delivering their genes
    to human cells in pathogenic matter.
  • Take advantage of this, manipulate genome to
    remove disease genes and insert therapeutic genes

14

15
Risks with GT trials
  • Viruses can usually infect more than one type of
    cell.
  • When DNA is injected directly into a tumor, there
    is a slight chance that this DNA could
    unintentionally be introduced into reproductive
    cells.
  • Other concerns include the possibility that
    transferred genes could be "overexpressed"

16

17
Add a new chromosome?
  • Experimentation seen with introduction of 47th
    chromosome
  • Exist along 46th chromosome, large vector capable
    carrying genetic code, that hopefully the immune
    system would not attack

18
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19
Understanding?
  • Scientists know little about function of the
    thousands of genes. Attempting therapy without
    this knowledge would address few genes of a
    particular disease
  • i.e. Sickle Cell Anemia

20
Sickle Cell Anemia
  • Caused by error in gene that informs our body on
    how to make hemoglobin
  • Prevalent in African Americans
  • However deadly the error is, this increased the
    survival rate for those who also had malaria in
    the region

21
Hurdles
  • Most genetic disorders involve more than one
    gene, only few genetic diseases involve merely
    one
  • This multigene disorders also involve the
    environment, such as diet, exercise, smoking, etc.

22
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23
Everything has a price
  • High costs associated with developing this
    technology, and regulations that needed to be
    implied on it with experimentations are great
    hurdles for experimenters in this field.

24
First Human Gene Therapy attempt
  • Began in 1990, using ex vivo strategy, where
    patient cells were cultivated in laboratory and
    incubated with vectors
  • transplanted back into the patient
  • Attempted to treat 2 genetic disorders, including
    children with immune defiency as well as people
    with high levels of serum cholesterol

25
First Human GT cont
  • Practical approaches, delivering genes based on
    so-called in vivo GT where viruses are directly
    given to patients
  • First model was dependent on a version of
    adenovirus to treat cystic fibrosis

26
GT on Cancer Treatment
  • Researchers are working to improve the body's
    natural ability to fight the disease or to make
    the cancer cells more sensitive to other kinds of
    treatment, such as chemotherapy
  • Substitution of a "working" copy of a gene for an
    inactive or defective gene.

27
GT on Cancer cont
  • Injection of cancer cells with a gene that makes
    them more sensitive to treatment with an
    anticancer drug.
  • Introduction of the multidrug resistance gene
    into stem cells. The MDR gene is used to make the
    stem cells more resistant to the side effects of
    the high doses of anticancer drugs.

28
Hurdles Summary
  • There are many obstacles that prevent researchers
    and scientist from developing successful gene
    therapy techniques.
  • The issues being confronted are the same ones
    that are faced whenever a powerful new technology
    is developed.

29
When All is Said
  • A proposed gene therapy trial, or protocol, must
    be approved by at least two review boards at the
    scientists' institution.
  • Any studies involving humans must be reviewed
    with great care.

30
CASE STUDY SCID
  • SCID Severe Combined Immunodeficiency

31
What is SCID?
  • SCID patients can neither
  • Construct cell-mediated immune response
  • Make Antibodies
  • Patients do not die of SCID itself
  • More Boys than Girls

32
SCID Cases, Past Present
  • Not discovered until early 1960s
  • Occur in 1 out of 1.000,000
  • Bubble Boy David Vetter
  • Spent 12 years in Texas Hospital Sterile Tent
  • Usually not discovered until too late

33
Science Behind SCID (1)
  • What Happens in SCID
  • Lymphocyte T B cells do not get developed
  • Normal catabolism of purines deficient
  • Body lack messenger to identify foreign bodies
  • Cannot initiate immune response

34
Science Behind SCID (2)
  • What Caused SCID?
  • ADA (Adenosine Deaminase) enzyme deficiency
  • Autosomal recessive inheritance of genes coding
    for ADA (25)
  • Cannot Make T cells
  • Spontaneous Mutation of IL-7 Gene

35
Science Behind SCID (3)

36
Science Behind SCID (4)

37
Possible Therapies
  • Gem free tent (life long)
  • Regular injections of PEG-ADA
  • Bone Marrow Transplant
  • Gene Therapy

38
GT Curing SCID (1)
  • How mutated genes were discovered?
  • Late 1970s understood mechanism for immune
    system
  • Match SCID to missing enzyme
  • Brute force / luck
  • 1983 ADA cDNA identified cloned

39
GT Curing SCID (2)
  • How mutations are corrected
  • Recombinant DNA technologies!!!
  • Gene Splicing
  • Insertion of correct gene into retrovirus vector
  • Separate Multiply
  • Insert into patient

40
GT Curing SCID (3)
  • How to decide on delivery mechanism?
  • Goals
  • Must take up long-term residence in patient
  • Must be expressed adequately
  • Methods
  • 1990 use patients own T cells (ADA)
  • 1993 use blood stem cells (ADA)
  • 1999 use blood stem cells (X-linked IL-7)

41
GT Curing SCID (4)
  • Gene Therapy Successes
  • So far approximately 80 success rate
  • Restoration of normal cellular immunity in
    patients
  • Blood Stem Cells Method done on an increasing
    scale

42
SCID Cure Analysis
  • Why GT works in SCID?
  • Defect at a single gene locus
  • Genes identified cloned
  • Undergo irradiation or immunosuppressive
    chemotherapy
  • Treatment of young children

43
Discussion of Ethical, Legal Social Issues
  • Many issues concerns, little answers
  • Real life solutions come from idea brainstorms
  • Today Sample Medical
  • System Framework

44
Current Development
  • Signs of Development
  • State Laws Federal Bills which prohibits
    discrimination based on genetic information
  • Special committee reviewing gene therapy (NIH
    FDA)
  • 3-5 of all funds for genetics studies must be
    used for investigation of such issues

45
Targeted Issues
  • Regulation of Gene Therapy
  • Assurance of Quality of Treatment
  • Targeted Treatment
  • Disease Treatment vs. Enhancement
  • Only Disease Treatment
  • Fair Readily Available Treatment
  • Same Treatment for everyone
  • At an affordable price
  • Protection of Genetic Information

46
Assumptions
  • Possible to isolate and provide treatment only
    for disease alleles without committing
    enhancement
  • Development in medical technologies will make
    medication cheaper in the long run
  • Model applies for a closed country only

47
Model Philosophy
  • Possession of genetic information causes many
    problems
  • Must have a tightly regulated system in place
    (multi-level, multi-group)
  • Proposal
  • Central Gene Therapy Monitoring Administration

48
Structure of Medical System
  • 3 Levels, 5 Groups
  • Government CGTMA Review Committee
  • Practitioners Doctors Gene Therapeutics
  • Patients Patients

49
Patient Treatment Process (1)
  • 7 Steps
  • Disease Identification
  • 1.1 Doctor Identifies Genetic Problem
  • Application for Treatment
  • 2.1 Doctor Submit Application
  • Treatment Approval
  • 3.1 CGTMA Reviews Application

50
Patient Treatment Process (2)
  • Preparation of Delivery Material
  • 4.1 Gene Therapeutics cure the disease genes,
    deliver to patients stem cell
  • Confirmation of Appropriate Changes
  • 5.1 CGTMA confirms for appropriate changes
  • Gene Therapy
  • 6.1 Doctor conducts Gene Therapy to Patient

51
Patient Treatment Process (3)
  • Checkup
  • 7.1 Confirm patients received only approved
    treatment (by CGTMA)

52
Groups Responsibility (1)
  • CGTMA
  • Check validity of genetic treatment (i.e. only
    targeting disease genes)
  • Check for appropriate preparation of genetic
    material for gene therapy
  • Monitor Treatment by Doctor
  • Review Committee
  • Determine disease genes vs. enhancement genes

53
Groups Responsibility (2)
  • Doctors
  • Identifying Disease
  • Submitting Application for Gene Therapy
  • Conducting Gene Therapy
  • Gene Therapeutics
  • Manipulate genes based on application
  • Both group faces penalty for illegal practices

54
Important Factors
  • Must have good internal and external monitoring
    by each group
  • Must be aware and implement policy for patients
    privacy rights
  • Education of the general public

55
Discussion QA
  • How model answers targeted issues
  • Flaws with the models
  • Discussion
  • Additional QA

56
End (Yeah finally)
  • Thanks for your patience !
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