Human genome project 2007


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Human genome project 2007

  1. 1. Human Genome Project Potential Applications
  2. 2. In March, 2002 <ul><li>Doctors successfully screened embryos for gene mutation linked to early onset Alzheimer's </li></ul><ul><li> JAMA, March, 2002 </li></ul>
  3. 3. Basics <ul><li>Inside the nucleus of every cell in the body, a complex set of genetic instructions, known as the human genome, contained on pairs of chromosomes. </li></ul>
  4. 5. Gene <ul><li>A gene is a chromosomal region capable of making a functional transcript. </li></ul>
  5. 9. However <ul><li>Many genes are co-expressed with their own antagonist </li></ul>
  6. 10. Thus <ul><li>A genome is all the DNA in the cell, including its genes. </li></ul><ul><li>Errors in genes--the smallest units of heredity-- may cause or contribute to disease </li></ul>
  7. 11. The result <ul><li>All diseases have a genetic component, whether inherited or resulting from the body's response to environmental stresses like viruses or toxins </li></ul>
  8. 12. Genomics <ul><li>Structural genomics : to identify all the approximate 30,000 genes in human DNA </li></ul><ul><li>Functional genomics : to understand gene-gene interaction </li></ul>
  9. 13. Objectives <ul><li>store this information in databases </li></ul><ul><li>Build up a genomic library </li></ul>
  10. 15. <ul><li>Once needed , investigators can simply go to the freezer where DNA for the physical map is stored and pick out the piece that contains the gene. </li></ul>
  11. 16. The most important question <ul><li>How & Which </li></ul><ul><li>genes play a role in disease causation </li></ul>
  12. 17. Tools <ul><li>An increasing number of gene tests are becoming available commercially </li></ul><ul><li>Micro-array composed of five separate array each of which has about 10,000 target </li></ul>
  13. 20. Genomic Medicine <ul><li>Diagnosis </li></ul><ul><li>Monitoring of progress </li></ul><ul><li>treatment of disease </li></ul><ul><li>Prevention </li></ul>
  14. 21. Example <ul><li>hereditary nonpolyposis colon cancer was linked to a gene located on chromosome 2. </li></ul>
  15. 22. But <ul><li>The road from gene identification to effective treatments is long and full of challenges </li></ul>
  16. 23. So Why?!!! <ul><li>We as Doctors must be aware about the new genetic era and its potential impacts on our specialty so as to offer our patients the most appropriate and informed care. </li></ul>
  17. 24. Implantation : the model <ul><li>Repeated failure of implantation was linked to Leukemia inhibitory Factor gene (LIF) </li></ul>
  18. 25. Implantation <ul><li>Micro-array analysis has shown 36 up-regulated genes and 27 down-regulated genes at the implantation site. </li></ul><ul><li>Reese J et al, 2001 </li></ul>
  19. 26. Categorised in <ul><li>genes with recognized roles in implantation, </li></ul><ul><li>genes with potential roles in this process </li></ul><ul><li>genes whose functions have yet to be defined in this event </li></ul>
  20. 27. polycystic ovary syndrome <ul><li>the insulin gene called variable number tandem repeat (VNTR) gene appears to be a promising candidate </li></ul>
  21. 28. polycystic ovary syndrome <ul><li>follistatin gene as a potential disease locus implicated in ovarian follicular development </li></ul>
  22. 29. polycystic ovary syndrome <ul><li>CYP11a gene -encoding P450 side chain cleavage-appears to be a major susceptibility locus for steroidogenic abnormalities </li></ul><ul><li>Franks et al, 2001 </li></ul>
  23. 30. MUC 1: a genetic link to infertility? <ul><ul><li>Women with unexplained infertility were found to have a genetic susceptibility to failure of embryo implantation due to small MUC 1 allele size. </li></ul></ul><ul><ul><li>Horne A, et al,2001 </li></ul></ul>
  24. 31. <ul><li>Inherited breast and ovarian cancer (BRCA 1 and 2; early-onset tumors of breasts and ovaries) </li></ul>
  25. 32. Pre-eclampsia <ul><li>A polymorphism in the gene for microsomal epoxide hydrolase is associated with pre-eclampsia </li></ul><ul><li>Zusterzeel et al 2001 </li></ul>
  26. 33. <ul><li>Women with the glutathione S-transferase P1b-1b genotype, which could result in lower glutathione S-transferase detoxification capacity, has been linked to higher susceptibility to preeclampsia </li></ul><ul><li>Zusterzeel 2000 </li></ul>
  27. 34. Gynecological oncology <ul><li>The increased ovarian cancer risk associated with the high-activity of human EPHX gene (epoxide hydrolase) </li></ul>
  28. 35. cystic fibrosis <ul><li>three hundred affected children born each year in UK </li></ul><ul><li>with improvements in care and treatment, people with cystic fibrosis can now live for up to twenty-five years, </li></ul><ul><li>there is no cure </li></ul>
  29. 36. PGD
  30. 37. Currently Available DNA-Based Gene Tests <ul><li>Alpha-1-antitrypsin deficiency </li></ul><ul><li>myotrophic lateral sclerosis </li></ul><ul><li>Alzheimer's disease </li></ul><ul><li>Cystic fibrosis </li></ul><ul><li>Myotonic dystrophy </li></ul><ul><li>Neurofibromatosis type 1 </li></ul><ul><li>Thalassemias </li></ul>
  31. 38. <ul><li>Ataxia telangiectasia </li></ul><ul><li>Gaucher disease </li></ul><ul><li>Hereditary nonpolyposis colon cancer </li></ul><ul><li>Charcot-Marie-Tooth </li></ul><ul><li>Congenital adrenal hyperplasia </li></ul>
  32. 39. <ul><li>Duchenne muscular dystrophy/Becker muscular dystrophy </li></ul><ul><li>Fanconi anemia </li></ul><ul><li>Factor V-Leiden </li></ul><ul><li>Fragile X syndrome </li></ul><ul><li>Hemophilia A and B </li></ul><ul><li>Huntington's disease </li></ul>
  33. 40. <ul><li>Phenylketonuria </li></ul><ul><li>Adult Polycystic Kidney Disease </li></ul><ul><li>Prader Willi/Angelman syndromes </li></ul><ul><li>Sickle cell disease </li></ul><ul><li>Spinocerebellar ataxia </li></ul><ul><li>Spinal muscular atrophy </li></ul><ul><li>Tay-Sachs Disease </li></ul>
  34. 41. Gene therapy It means modification of the genetic material of living cells This applies to genetically determined diseases but may also expanded to diseases that occur later in life
  35. 42. Highly promising <ul><li>Treatment </li></ul><ul><li>Prevention </li></ul><ul><li>Immunity enhancing (e.g., by adding a gene that suppresses tumor growth). </li></ul>
  36. 43. Still experimental <ul><li>more technological barriers are encountered than foreseen and therefore, the clinical success up to now is limited. </li></ul>
  37. 44. Germ cell gene therapy
  38. 45. Germ cell gene therapy
  39. 46. <ul><li>Deposit corrective genes in the cell’s nucleus, </li></ul><ul><li>integrate genes into the chromosomes.. </li></ul>
  40. 47. Somatic cell gene therapy The Concept Natural ability of viruses to enter cells through receptors genetically altered to carry normal human DNA.
  41. 48. How it is prepared!! <ul><li>harmful viral genes are removed and replaced with the corrective gene. (Vector) </li></ul>
  42. 50. <ul><li>Viruses recognize and attach to receptors (a) and work their way through, into the cell (b). Once inside, the virus discharges its contents (c). Viral genes progress through the cell and into the nucleus (d). </li></ul>
  43. 51. How to select <ul><li>Depending on the specific virus, these genes may or may not integrate into the host's chromosomes. </li></ul>
  44. 52. Specific Target <ul><li>Each virus is particularly adapted to use one or a few specific receptors, which limits the range of cells each one can infect. </li></ul>
  45. 54. How <ul><li>Cells may be modified ex vivo for subsequent administration to patients, or may be altered in vivo by gene therapy given directly to the subject. </li></ul>
  46. 55. Familial Hypercholesterolemia <ul><li>A retroviral vector delivers a corrective low-density lipoprotein (LDL) receptor gene. </li></ul><ul><li>A piece of the patient's </li></ul><ul><li>liver is removed, and the cells </li></ul><ul><li>are treated with a retrovirus </li></ul><ul><li>carrying a good copy of the </li></ul><ul><li>gene. </li></ul><ul><li>Liver cells incorporating </li></ul><ul><li>the corrective gene are </li></ul><ul><li>implanted into the patient's </li></ul><ul><li>liver. </li></ul>
  47. 59. It is the future <ul><li>Currently, within the context of clinical trials, (FDA) has not yet approved any human gene therapy product for sale. </li></ul><ul><li>gene therapy for single-gene diseases will be routine and successful within years. </li></ul>
  48. 60. Role in oncology <ul><ul><li>It has been proven that many cancers are caused by the mutation of certain genes or lack of gene function </li></ul></ul><ul><ul><li>The introduction of those genes into cancer cells where gene function is compromised, can work to restore gene function and stop tumor progression </li></ul></ul>
  49. 61. May be in the future <ul><li>Patients with cancer may receive combination chemotherapy together with gene therapy for six cycles of treatment </li></ul><ul><li>Ozols 2002 </li></ul>
  50. 62. Gene Therapy: Simple in Theory but Difficult in Practice
  51. 63. Obstacles <ul><li>Safety </li></ul><ul><li>Short-lived nature of gene therapy </li></ul><ul><li>Multigene disorders </li></ul><ul><li>Costs </li></ul><ul><li>Ethics : Baby designers </li></ul>
  52. 64. Safety <ul><li>In a gene therapy trial for ornithine transcarboxylase deficiency (OTCD). An 18 years old boy died from multiple organ failures after starting the treatment. (? severe immune response to the adenovirus carrier) </li></ul>
  53. 65. <ul><li>A child successfully treated by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID), known as &quot;bubble baby syndrome.&quot; developed a leukemia-like condition. </li></ul>
  54. 66. Nonviral approach (2003) <ul><li>involves the creation of an artificial lipid sphere with an aqueous core. This liposome, which carries the therapeutic DNA, is capable of passing the DNA through the target cell's membrane </li></ul><ul><li>potential for treating Parkinsonism </li></ul>
  55. 67. Where we stand!! <ul><li>all of the current approaches to gene therapy seek to introduce the good gene into the so-called somatic cells of a child or an adult. </li></ul><ul><li>While somatic gene therapy is thought to be appropriate, germ line gene therapy is not allowed </li></ul>
  56. 68. More Effective Pharmaceuticals <ul><li>Efforts will shift toward developing a new generation of therapeutics based on genes. </li></ul>
  57. 69. How <ul><li>doctors will test individual genetic profiles against panels of drugs available for a specific condition and choose the treatment with the greatest potential benefit. </li></ul><ul><li>antihypertensives </li></ul>
  58. 70. It is real <ul><li>All will be manufactured by recombinant DNA technology just as human insulin and growth hormone are today </li></ul>
  59. 72. Stem Cells Alzheimer’s Disease Parkinson’s Disease Various Leukemias Hodgkin’s Lymphoma Non-Hodgkin’s Lymphomas Heart Disease Diabetes Multiple Sclerosis Huntington’s Disease Osteoarthritis Coeliac Disease Crohn’s Disease Lupus Erythematosus Sickle Cell Anaemia Thalassemia Blackfan Diamond Anaemia Fanconi Anaemia
  60. 73. Types of Stem Cells Pluripotent Stem Cells: Can give rise to all different cell types in vitro . Multipotent Stem Cells: Can give rise to several cell types of a tissue or organ. Unipotent Stem Cells: consist of a single cell type only.
  61. 74. Sources of Stem Cells <ul><li>Blastocyst embryos - pluripotent </li></ul><ul><li>Foetal tissues - pluripotent or multipotent </li></ul><ul><li>Umbilical cord blood - multipotent </li></ul>
  62. 75. Isolation of Embryonic Stem Cells Embryonic Stem cells Culture Inner Cell Mass BLASTOCYST 5-7 day old embryo
  63. 76. Differentiation of E.S.C. Using particular treatment regimes, embryonic stem cells can be made to differentiate into many types of cell. This is because they are pluripotent . Embryonic Stem Cells Liver Cells Muscle cells Skin cells
  64. 79. Thank you!!