Gene therapy lecture_spring_2007
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Transcript of Gene therapy lecture_spring_2007
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APPLICATIONS FOR GENE THERAPY
Felix KriedemannGonzalo Briones11ºA
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Gene Therapy
Objectives:
1. Recognize significance and uses of gene therapy.
2. Define background theory and methodologies.
3. Address potential clinical applications, limitations, and future directions.
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Objectives of gene therapy:
1. Management and correction of human diseasesa. Inherited and acquired disordersb. Cancerc. AIDS/HIV
Good news: Promising advances during the last two decades in making DNA technology.
Bad news: Efficacy in any gene therapy protocol not definitive.
1. Inadequate understanding of biological interactions of vector and host.
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(27)(86)
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Some global terms/definitions:
1. Genes and nucleic acids2. Vector, viral delivery systems3. Gene transfer4. Reporter gene5. Transfer efficiency6. Germ vs. somatic cells7. In/ex vivo, in situ, in vitro.
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Genetic diseases:
Type 1: Single locus (gene) is defective and responsible for the disease, 100% heritable.
examples: Sickle cell anemia, HypercholesterolemiaCystic fibrosis
Type 2: Polygenic traits, less than 100% heritable, may be dependent on environmental factors and lifestyle.
examples: Heart diseaseCancerDiabetesAlcoholismSchizophreniaCriminal behavior?etc….?
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How it works ?
Transcription(nucleases)
Exogenous DNA+ vector (viral)
Cytosol
Endosome
Lysosome
Protein expression
Barriers that prevent transfer of exogenous DNA
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Categories of clinical gene transfer protocols.
1. Inherited/monogenic disorders: ADA deficiencyAlpha-1 antitrypsinChronic granulomatous diseaseCystic fibrosisFamilial hypercholesterolemiaFanconi AnemiaGaucher DiseaseHunter syndromeParkinsons
2. Infectious Diseases:HIV
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4. Cancer (by approach):
Antisense
Chemoprotection
Immunotherapy: ex vivo / in vivo
Thymidylate kinase
Tumor suppressor genes
3. Acquired disorders:peripheral artery diseaseRheumatoid arthritis
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‘Cancer regression in patients after transfer of genetically engineered lymphocytes.’
Liver
Lymphnode
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Case study: Jesse Gelsinger
*First documented patient to die from gene therapy treatment.
Disease: liver enzyme deficiency (ornithine transcarbamylase, OTC) –
controls ammonia metabolism
Vector used to deliver OTC – modified adenovirus
Objective: deliver vector to liver cells and express OTC.
Problem: Very low transfer efficiency (1%), difficult to getenough functioning OTC expressed to do any good.
Solution: Infect with higher dose of viral particles. (38 trillion)
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Outcome:
-Vector not only delivered gene to liver but to other tissue.- Systemic inflammatory response.-Patient acquired fever, coma and finally death.
Why?
-Animal studies suggested that the dose was correct .-Adenoviral vectors known to induce inflammatory response.-Patient already compromised:
Patient had higher than allowed ammonia levels.
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BibliographyAnd, A. (1994). Gene Therapy: Some History, Applications, Problems, and Prospects. [online] Retrieved from: http://tpx.sagepub.com/content/36/1/97.full [Accessed: 2 Apr 2013].
Herkules.oulu.fi (1997). Applications of somatic gene therapy. [online] Retrieved from: http://herkules.oulu.fi/isbn9514255429/html/x298.html [Accessed: 2 Apr 2013].
Intechopen.com (2012). What is Gene Therapy | Applications | InTechOpen. [online] Retrieved from: http://www.intechopen.com/books/gene-therapy-applications [Accessed: 2 Apr 2013].
Iptv.org (2004). Gene Therapy » Medical Uses of GE » Uses » Explore More: Genetic Engineering. [online] Retrieved from: http://www.iptv.org/exploremore/ge/uses/use2_gene.cfm [Accessed: 2 Apr 2013].
MedicineNet (2013). Gene Therapy - The Future Is Here!. [online] Retrieved from: http://www.medicinenet.com/script/main/art.asp?articlekey=12662 [Accessed: 2 Apr 2013].
YouTube (n.d.). Vector design for vaccine and gene therapy applications. [online] Retrieved from: http://www.youtube.com/watch?v=zKLpRufcy0k [Accessed: 2 Apr 2013].