Genomics could be difficult to understand for gynecologists. In this talk we will try to make it simple .

1. Human Genome
Project
Potential Applications

2. In March, 2002
Doctors successfully screened embryos
for gene mutation linked to early onset
Alzheimer's
JAMA, March, 2002

3. A Great Success

4. Basics
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.

6. Chromosomes are long chains of
DNA-deoxyribonucleic acid.

9. Base code
Hereditary instructions are written in
a four-letter code, with each letter
corresponding to one of the
chemical constituents of DNA: A, G,
C, T.

11. Gene
A gene is a chromosomal region
capable of making a functional
transcript.

14. Thus
A genome is all the DNA in the cell,
including its genes.
Errors in genes--the smallest units of
heredity-- may cause or contribute to
disease

17. However
Many genes are co-expressed with their
own antagonist

18. The result
All diseases have a genetic component,
whether inherited or resulting from the
body's response to environmental
stresses like viruses or toxins

19. Genomics
Structural genomics: to identify all the
approximate 30,000 genes in human
DNA
Functional genomics: to understand
gene-gene interaction

20. Objectives
determine the sequences of the 3 billion
chemical base pairs that make up
human DNA,
store this information in databases
explore potential application in
practical life

22. The concept
How & Which
genes play a role in disease
causation

23. Tools
An increasing number of gene tests are
becoming available commercially
Micro-array composed of five separate
array each of which has about 10,000
target

26. Genomic Medicine
Diagnosis
Monitoring of progress
treatment of disease
Prevention

27. Example
Using tools emerging from the Human
Genome Project, an international team
tracked the gene for hereditary
nonpolyposis colon cancer to a region
of chromosome 2.

28. But
The road from gene identification to
effective treatments is long and full of
challenges

29. So Why?!!!
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.

30. Implantation : the model
Repeated failure of implantation was
linked to Leukemia inhibitory Factor
gene (LIF)
However,

31. Implantation
Micro-array analysis has shown 36 up-
regulated genes and 27 down-regulated
genes at the implantation site.
Reese J et al, 2001

32. Categorised in
genes with recognized roles in
implantation,
genes with potential roles in this
process
genes whose functions have yet to be
defined in this event

33. Polycystic Ovary
Syndrome
the insulin gene called variable number
tandem repeat (VNTR) gene appears to
be a promising candidate

34. Polycystic Ovary
Syndrome
follistatin gene as a potential disease
locus implicated in ovarian follicular
development

35. Polycystic ovary
syndrome
CYP11a gene -encoding P450 side
chain cleavage-appears to be a major
susceptibility locus for steroidogenic
abnormalities
Franks et al, 2001

36. MUC 1: a genetic link to
infertility?
Women with unexplained infertility were
found to have a genetic susceptibility to
failure of embryo implantation due to
small MUC 1 allele size.
Horne A, et al,2001

37. Inherited breast and ovarian cancer
(BRCA 1 and 2; early-onset tumors of
breasts and ovaries)

38. Pre-eclampsia
A polymorphism in the gene for
microsomal epoxide hydrolase is
associated with pre-eclampsia
Zusterzeel et al 2001

39. 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
Zusterzeel 2000

40. Gynecological oncology
The increased ovarian cancer risk
associated with the high-activity of
human EPHX gene (epoxide hydrolase)

41. Cystic Fibrosis
three hundred affected children born each year
in UK
Although improvements in care and treatment mean that people with cystic fibrosis can now live
for up to twenty-five years,
there is no cure

42. Currently Available
DNA-Based Gene Tests
Some Alpha-1-antitrypsin deficiency
Alzheimer's disease
Cystic fibrosis

43. Ataxia telangiectasia
Gaucher disease
Inherited breast and ovarian cancer
Hereditary nonpolyposis colon cancer
Charcot-Marie-Tooth
Congenital adrenal hyperplasia

44. Duchenne muscular dystrophy/Becker
muscular dystrophy
Fanconi anemia
Factor V-Leiden
Fragile X syndrome
Hemophilia A and B
Huntington's disease
Myotonic dystrophy
Neurofibromatosis type 1

45. Phenylketonuria
Adult Polycystic Kidney Disease
Prader Willi/Angelman syndromes
Sickle cell disease Spinocerebellar ataxia
Spinal muscular atrophy
Thalassemias
Tay-Sachs Disease

46. Gene Therapy
It means modification of the genetic
material of living cells
This applies to genetically determined
diseases but also to diseases that occur
later in life

47. Highly promising
Treatment
Prevention
Immunity enhancing (e.g., by adding a
gene that suppresses tumor growth).

48. Still experimental
more technological barriers are
encountered than foreseen and
therefore, the clinical success up to now
is limited.

49. How
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.

51. Germ cell gene therapy

52. Two techniques
Deposit corrective
genes in the cell’s
nucleus,
integrate genes into
the chromosomes..

53. Somatic cell gene
therapy

54. Vector
Viral genes targeting
the cell's nucleus
are retained in the
vector, while harmful
viral genes are
removed and
replaced with the
corrective gene.

56. Steps
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).

57. Specific Target
Each virus is particularly adapted to use
one or a few specific receptors, which
limits the range of cells each one can
infect.

58. Familial
Hypercholesterolemia
A corrective low-
density lipoprotein
(LDL) receptor gene.
A piece of the
patient's liver was
removed, and the
cells were treated with
a retrovirus carrying a
good copy of the
gene. Cells with the
corrective gene were
reimplanted into the
patients's liver.

59. Is it the future!!!
gene therapy for single-gene diseases
may be routine and successful in 20
years.

61. Role in oncology
• It has been proven that many cancers are
caused by the mutation of certain genes or
lack of gene function
• The introduction of those genes into cancer
cells where gene function is compromised,
can work to restore gene function and stop
tumor progression

62. Cancer Gene Therapy
• The RIZ1 gene is the best example
• has potent tumor suppressive activities in
causing apoptosis, G2/M arrest, or both.
• Preclinical animal studies have shown that
a recombinant adenovirus expressing the
gene, AdRIZ1, can suppress
the growth of colon cancer
Canote 2002

63. May be in the future
Patients with cancer may receive
combination chemotherapy together
with gene therapy for six cycles of
treatment and, at that point, the
chemotherapy is stopped and patients
continue with chronic maintenance
biologic therapy
Ozols 2002

64. Gene Therapy: Simple
in Theory but Difficult
in Practice

65. Obstacles
Safety
Costs
Ethics : Baby designers

66. 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.