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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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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].