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GENE THERAPY By Sam Lai and Meng Lee
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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 / Q&A
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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
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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 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.
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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
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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
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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.
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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.
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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
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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
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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
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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"
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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
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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
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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
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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.
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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.
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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
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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
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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.
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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.
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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.
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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.
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CASE STUDY: SCID SCID = Severe Combined Immunodeficiency
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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
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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
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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
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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
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Science Behind SCID (3)
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Science Behind SCID (4)
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Possible Therapies Gem free tent (life long)
Regular injections of PEG-ADA Bone Marrow Transplant Gene Therapy
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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
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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
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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 patient’s own T cells (ADA) 1993 – use blood stem cells (ADA) 1999 – use blood stem cells (X-linked IL-7)
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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
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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
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Discussion of Ethical, Legal & Social Issues
Many issues & concerns, little answers Real life solutions come from idea brainstorms Today: Sample Medical System Framework
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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
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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
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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
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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
3 Levels, 5 Groups Government: CGTMA Review Committee Practitioners: Doctors Gene Therapeutics Patients: Patients
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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
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Patient Treatment Process (2)
Preparation of Delivery Material 4.1 Gene Therapeutics cure the disease genes, deliver to patient’s stem cell Confirmation of Appropriate Changes 5.1 CGTMA confirms for appropriate changes Gene Therapy 6.1 Doctor conducts Gene Therapy to Patient
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Patient Treatment Process (3)
Checkup 7.1 Confirm patients received only approved treatment (by CGTMA)
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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
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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
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Important Factors 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
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Discussion + Q&A How model answers targeted issues
Flaws with the models Discussion Additional Q&A
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End (Yeah finally…) Thanks for your patience !
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