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| Jesse Gelsinger |
partial OTC deficiency |
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mcs5109 Sun, 01 Nov 2009 06:25:26 GMT |
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| Rhys Evans |
SCID |
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mcs5109 Sun, 01 Nov 2009 06:25:26 GMT |
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| • Allogeneic transplants |
-stem cells received from brother, sister or parent, or, if necessary, and unrelated donor. |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| • Syngeneic transplants |
patients receive
stem cells from their identical twin |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| • Autologous transplants |
- patients receive their own stem cells |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| 3 Graft Types |
Autologous transplant
Syngeneic transplants
Allogeneic transplants |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| Hematapoietic Stem Cells |
• Different from embryonic stem cells
• Found in bone marrow, blood and
umbilical cord blood
• Can mature into three types of blood cells
– White blood cells
– Red blood cells
– Platelets |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| • Liposomes |
– No limit to the amount of DNA that can be packaged
– Lipid-based, similar to cellular membrane
– Not specific, but does not enter cells as effectively as viral vectors
– Not immunogenic, but may be toxic
– Needs to be integrated to allow DNA to integrate
– May be best suited for ex vivo therapies
-no size limit
-no immune reponse b/c no proteins
-can't replicate/recombine so less risk of infectious form
-hard to infect in vivo
-inefficient
-can't target tissues |
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mcs5109 Mon, 02 Nov 2009 04:35:57 GMT |
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| • Naked DNA |
– Plasmid
– Some cells will take up, but not specific
– No maximum
– Little or no integration
– No immunogenicity or toxicity
– Best for ex vivo |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| • Adeno-associated virus |
– Does not cause illness
– Dividing and resting cells
– Can target specific cells
– 90% integration into chromosome 19
– Usually no immune response
– Max capacity 5 kb
-small amt DNA allowed
-no viral genes
-safe
-non-dividing cells
-stable expression
-labor-intensive |
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mcs5109 Mon, 02 Nov 2009 04:26:00 GMT |
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| • Adenovirus |
– Both dividing and resting cells
– Can target specific types of cells
– Does not integrate into DNA
– Causes immune response
– Max capacity 7.5 kb
-responsible for respiratory infections
-efficient
-high titer
-don't integrate into DNA
low level of viral antigens produces robust immune response that eliminated transduced cells
-delete viral genes that are most immunogenic?
-but, there will always be some level of immunity |
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mcs5109 Mon, 02 Nov 2009 04:22:38 GMT |
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| • Retroviral vectors |
– Target actively dividing cells
– RNA must be converted to DNA before activation
– Random integration
– Causes immune response
– Max capacity: 8 kb
-only transduce dividing cells
-but, most in vivo cells are quiescent!
-but, low titer |
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mcs5109 Mon, 02 Nov 2009 04:10:26 GMT |
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| Viral Vectors for Gene Therapy |
-Retroviral vectors
-Adenovirus
-Adeno-associated virus
-Herpes simplex virus |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| • Herpes simplex virus |
– Targets nervous cells
– Will not integrate, but can remain episomal, will be copied and passed on
– Causes immune response
– Max capacity 20 kb |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| First gene therapy approval |
(1990)- Ashanti de Silva
-ADA deficiency |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| ADA deficiency |
• Adenosine deaminase (ADA) deficiency
-one form of SCID (severe combined
immunodeficiency)
• Adenosine deaminase breaks down a toxic substance, deoxyadenosine
• Autosomal recessive disease (inherit one copy from each parent)
• Most babies die within months
• rare |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| Nonviral Vectors |
-Liposomes
-Naked DNA |
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mcs5109 Sun, 01 Nov 2009 06:23:57 GMT |
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| SCID patients (bubble boy) |
-gene therapy was successful, but 2 patients got leukemia due to improper integration of gene |
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mcs5109 Sun, 01 Nov 2009 06:12:24 GMT |
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| Jesse Gelsinger |
rare liver disorder, died in 1999 as
a result of immune response to gene therapy |
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mcs5109 Sun, 01 Nov 2009 06:12:24 GMT |
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| Problems w/gene therapy in the past |
-delivery method
-activation of gene expression
– Introducing gene in correct cells
– Immune response (Jesse)
– Disrupting other important genes (bubble boy) |
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mcs5109 Sun, 01 Nov 2009 06:12:24 GMT |
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| • In vivo versus ex vivo therapies |
– In vivo- cells are treated in patient’s body
– Ex vivo- cells are removed, treated and put back into patient |
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mcs5109 Sun, 01 Nov 2009 06:12:24 GMT |
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| • Necessary components of Gene Therapy |
– Target the appropriate cells/tissues
– Activate gene expression
– Integrate the gene into the DNA
– Avoid harmful side effects (immune response) |
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mcs5109 Sun, 01 Nov 2009 06:12:24 GMT |
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| • Gene inhibition therapy |
– Infectious diseases, cancer & inherited disorders
– Gene product inhibits or interferes w/defect |
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mcs5109 Sun, 01 Nov 2009 06:12:24 GMT |
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| • Gene augmentation therapy |
– Inherited disorders caused by loss of function
– Only if effects are reversible |
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mcs5109 Sun, 01 Nov 2009 06:12:24 GMT |
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| Types of Gene Therapy |
• Killing of specific cells (like cancer)
• Somatic and germ line therapy
• Gene augmentation therapy
• Gene inhibition therapy |
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mcs5109 Sun, 01 Nov 2009 06:12:24 GMT |
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| How is gene therapy used to treat disease? |
-A normal gene is inserted into a nonspecific location to replace nonfunctional gene.
– A normal gene may be swapped for an abnormal copy through homologous recombination
– Abnormal gene can be repaired
– The regulation of gene could be altered |
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mcs5109 Sun, 01 Nov 2009 06:12:24 GMT |
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| Gene Therapy |
– Technique for correcting defective genes responsible for disease development |
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mcs5109 Sun, 01 Nov 2009 06:12:24 GMT |
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| Level 3 Genetic Disorder |
-Multifactorial disorders
– Mutations in multiple genes, often w/
environmental factors (many cancers, alzheimer |
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mcs5109 Sun, 01 Nov 2009 05:57:45 GMT |
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| Level 2 Genetic Disorder |
-Chromosomal abnormalities
– Entire chromosomes or large segments are missing, duplicated or altered (ex: Down syndrome, cri-du-chat) |
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mcs5109 Sun, 01 Nov 2009 05:57:45 GMT |
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| Level 1 Genetic Disorder |
-Single gene disorders
– Mutation results in protein product being altered or missing (ex: ADA, SCID, Huntingdon’s disease, cystic fibrosis) |
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mcs5109 Sun, 01 Nov 2009 05:57:45 GMT |
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| Modes of Inheritance |
• Dominant
• Recessive
• X-linked recessive
• X-linked dominant
• Y-linked |
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mcs5109 Sun, 01 Nov 2009 05:57:45 GMT |
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