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GENE
THERAPY
By Sam Lai and Meng Lee
Gene Therapy
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Introduction : What is it?
Gene Therapy : A Closer Look
How much did you learn?!
Case Study : SCID
Model for Gene Therapy Medical
Framework
Discussion / Q&A
What is it?
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Gene therapy, which was first conceived in the mid1970s, 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
Human Genome Project
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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 person’s 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.
HGP GOALS
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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
HGP cont…
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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
Which Cells Targeted?
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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.
Somatic Stem Cells
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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.
Germline Gene Therapy
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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
Delivery of Genes
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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
Use of Viruses
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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
Risks with GT trials
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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"
Add a new chromosome?
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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
Understanding?
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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
Sickle Cell Anemia
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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
Hurdles…
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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.
Everything has a price
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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.
First Human Gene
Therapy attempt
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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
First Human GT cont…
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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
GT on Cancer Treatment
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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.
GT on Cancer cont…
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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.
Hurdles Summary
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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.
When All is Said…
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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.
CASE STUDY: SCID
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SCID = Severe Combined Immunodeficiency
What is SCID?
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SCID patients can neither
– Construct cell-mediated immune response
– Make Antibodies
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Patients do not die of SCID itself
More Boys than Girls
SCID Cases, Past & Present
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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
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Usually not discovered until
too late
Science Behind SCID (1)
What Happens in SCID
 Lymphocyte T & B cells do not get
developed
– Normal catabolism of purines deficient
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Body lack messenger to identify
foreign bodies
Cannot initiate immune response
Science Behind SCID (2)
What Caused SCID?
 ADA (Adenosine Deaminase) enzyme
deficiency
– Autosomal recessive inheritance of genes
coding for ADA (25%)
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Cannot Make T cells
– Spontaneous Mutation of IL-7 Gene
Science Behind SCID (3)
Science Behind SCID (4)
Possible Therapies
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Gem free tent (life long)
Regular injections of PEG-ADA
Bone Marrow Transplant
Gene Therapy
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
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
GT Curing SCID (3)
How to decide on delivery mechanism?
 Goals:
– Must take up long-term residence in patient
– Must be expressed adequately
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Methods:
– 1990 – use patient’s own T cells (ADA)
– 1993 – use blood stem cells (ADA)
– 1999 – use blood stem cells (X-linked IL-7)
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
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
Discussion of Ethical,
Legal & Social Issues
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Many issues & concerns, little answers
Real life solutions come from idea
brainstorms
Today: Sample Medical
System Framework
Current Development
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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
Targeted Issues
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Regulation of Gene Therapy
– Assurance of Quality of Treatment
– Targeted Treatment
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Disease Treatment vs. Enhancement
Only Disease Treatment
Fair & Readily Available Treatment
– Same Treatment for everyone
– At an affordable price
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Protection of Genetic Information
Assumptions
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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
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
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Structure of Medical System
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3 Levels, 5 Groups
Government:
CGTMA
Review Committee
Practitioners:
Doctors
Gene Therapeutics
Patients:
Patients
Patient Treatment Process (1)
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7 Steps
1. Disease Identification
1.1 Doctor Identifies Genetic Problem
2. Application for Treatment
2.1 Doctor Submit Application
3. Treatment Approval
3.1 CGTMA Reviews Application
Patient Treatment Process (2)
4.
Preparation of Delivery Material
4.1 Gene Therapeutics cure the disease genes,
deliver to patient’s stem cell
5.
Confirmation of Appropriate Changes
5.1 CGTMA confirms for appropriate changes
6.
Gene Therapy
6.1 Doctor conducts Gene Therapy to Patient
Patient Treatment Process (3)
7.
Checkup
7.1 Confirm patients received only approved
treatment (by CGTMA)
Groups Responsibility (1)
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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
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Review Committee
– Determine disease genes vs. enhancement
genes
Groups Responsibility (2)
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Doctors
– Identifying Disease
– Submitting Application for Gene Therapy
– Conducting Gene Therapy
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Gene Therapeutics
– Manipulate genes based on application
Both group faces penalty for illegal practices
Important Factors
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Must have good internal and external
monitoring by each group
Must be aware and implement policy
for patient’s privacy rights
Education of the general public
Discussion + Q&A
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How model answers targeted issues
Flaws with the models
Discussion
Additional Q&A
End (Yeah finally…)
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Thanks for your patience !