Pharmacogenomics and Gene Therapy (2011/2012)

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Course code
4S000712
Name of lecturer
Donato Zipeto
Coordinator
Donato Zipeto
Number of ECTS credits allocated
6
Academic sector
BIO/11 - MOLECULAR BIOLOGY
Language of instruction
Italian
Period
II semestre dal Mar 1, 2012 al Jun 15, 2012.

Lesson timetable

II semestre
Day Time Type Place Note
Wednesday 9:30 AM - 11:30 AM lesson Lecture Hall F from Mar 7, 2012  to Jun 15, 2012
Thursday 3:30 PM - 5:30 PM lesson Lecture Hall F from Mar 7, 2012  to Jun 15, 2012

Learning outcomes

Pharmacogenomics
1) Basic facts about pharmacogenimics and pharmacogenetics
2) Main drug classes and their molecular targets
3) Genetic basis of inter-individual variability in drug response
4) Genetic polymorphism in genes coding for phase I and II enzymes
5) Genetic models for the development of new drugs

Gene Therapy:
1) Basic facts about cell and gene therapy
2) Aims and limits of gene therapy
3) Tools used in gene therapy
4) Applications
5) Stem cells and their therapeutic use

Syllabus

1. Pharmacogenomic: introduction
• Definition
• Origin and history
• “Trial and error” vs personalized medicine
• Adverse drug reactions
• Pharmacokinetics and Pharmacodynamics
• Pharmacogenetics and Pharmacogenomics
• Objectives
• Clinical trials

2. Human genome
• Human genome project
• Sequencing methods
• New sequencing techniques
• Human genome organization
• Shotgun e Contig
• Gene prediction

3. Polymorphisms
• Gene variability
• Polymorphisms
• SNPs
• Genes influencing drug response
• Haplotypes

4. Difference in individual response
• Genomics technologies
• Microarray
• Therapeutic range
• Enzyme-drug interactions
• Biotransformation
• Variability
• Folic acid metabolism
• Ethanol metabolism

5. Cytochrome P450 (1(2)
• Generality, reactions, nomenclature
• Polymorphisms
• CYP2C19
• Proton pump inhibitors
• CYP2C9
• Anticoagulants (Warfarin, Ibuprofen, Phenytoin, Carbamazepine)
6. Cytochrome P450 (2/2)
• CYP2D6
• Codein
• CYP34A e 35A
• Statins

7. Neurodegenerative diseases and antitumor drugs
• Alzheimer
• Tamoxiflen
• TK inhibitors: Glivec
• EGFR: Gefitinib e Erlotinib
• Anti-cancer monoclonal antibodies
• ALK: crizotinib
• MDR-1 and NAT

8. TPMT, asthma
• TPMT: thiopurines
• TPMT polymorphisms
• Asthma
• Genes
• Beta2 adrenergic receptor
• 5-Lipoxygenase
• Glucocorticoids receptor

9. Anti-HIV therapy
• HIV and AIDS
• Host and viral genome
• Anti-HIV treatment
• Virus resistance
• HIV variability
• HAART
• Adverse reaction
• Natural resistance
• Abacavir hypersensitivity
• MDR1 and HIV

10. Future prospectives
• Pharmacogenomics
• Polygenic determinants
• Difficulties
• Resources
• Pharma industry
• Drug development
• Pharmacogenomics in scientific literature
• Current and future application in pharmacogenomics
• Comments, obstacles, education

11. Gender therapy, ethnicity, etic considerations
• Gender therapy
• Research
• Adverse reactions and gender
• Ethnic differences
• Slavery Hypertension Hypothesis
• Etic problems
• Genetic tests
• Patents
• Privacy
• Considerations
• Etic, legal and social implications

12. Introduction to gene therapy
• Definition and goals
• Clinical trials
• Applications
• Vectors
• Gene therapy in vivo and ex vivo
• Example: ADA
• Transgenes
• Somatic and germ cells
• Technical difficulties
• Future perspectives
• Etic considerations

13. Cell cultures, gene control, vectors
• Cell cultures
• Sterility
• Conditions
• Primary cultures and immortalized cultures
• Techniques
• Crio-preservation
• Mycoplasmas
• Cell banking
• Control of gene expression
• Promoters
• Vectors in gene therapy

14. Non-viral vectors and siRNA
• Non-viral vetors
• Plasmid
• Electroporation
• Liposomes
• Amine
• Anti-sense therapy
• RNA interference
• Viral vectors: introduction

15. Adeno and adeno-associated vectors
• Adenovirus
• Adenoviral vectors
• First and second generation adenoviral vectors
• Helper virus
• Toxicity
• PEGhilation
• Adeno-associated virus
• Recombinant AAV

16. Gene therapy of metabolic diseases
• Metabolic diseases
• Phenylketonuria
• Urea cycle defects
• Crigler-Najjar
• Glycogen storage disease

17. Retroviral and lentiviral vectors
• Other vectors: herpes simplex, poxvirus
• Retrovirus
• Genome and viral proteins
• Infetious cycle
• Retroviral vectors
• Helper
• Retroviral vector construction
• Lentivirus
• HIV, regulation
• First, second and third generation lentiviral vectors
• Multiple genes
• Integration
• Lentiviral vectors and therapy
• HIV to fight HIV

18. Gene therapy of infectious and hematopoietic diseases, cystic fibrosis
• Gene therapy of HIV
• Gene therapy of hematopoietic diseases
• β-thalassemia
• Trial in animal models
• Clinical trial phase I
• Cystic fibrosis
• Clinical manifestations
• Animal models
• Gene therapy

19. Neuromuscular and cardiac diseases
• Dystrophies
• Duchenne/Becker muscular dystrophy
• DMD
• Isoforms
• Animal models
• Therapy
• Utrofin
• Cell therapy DMD
• Gene therapy DMD
• Cardiovascular disease
• Atherosclerosis
• Animal models
• Gene therapy atherosclerosis

20. Stem cells
• Stem cells: origin
• Stem cells: definition
• Embryonic Stem Cells
• iPS cells
• Differentiation
• Therapeutic application
• Adult stem cells
• Stem cells niche
• Tissue engineering

21. Cell therapy and regenerative therapy
• Regenerative therapy
• Hematopoietic stem cells
• Mesenchymal stem cells
• iPS and reprogramming
• Epidermis regeneration
• Cornea regeneration
• Cardiac tissue regeneration
• Pancreatic tissue regeneration
• Bone tissue regeneration

22. Gene therapy of solid tumors
• Stem cells and cancer
• Wnt signaling
• Proliferation and progression
• Experimental therapies
• Antisense
• Chemoprevention
• Immunity
• Suicide genes
• Oncosuppressors
• P53

Therapeutic cloning
• Cloning
• Somatic cell nuclear transfer (SCNT)
• Cloning: classification
• Reproductive cloning
• Therapeutic cloning
• Cloned species
• Applications, problems
• Ethic considerations
• Future perspectives

24. Experimental applications
• Retroviral and lentiviral vectors: experimental applications
• Antitumor vaccination and tumor therapy

Assessment methods and criteria

Oral: thorough discussion on a specific topic, general questions on other topics treated.