Genetic Testing and Counseling, and Gene Therapy

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Genetic Testing and Counseling, and Gene Therapy

• By Jeraun Hudson, Brian Smith, and Thomas

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Genetic Testing

• Newborn screening is integrated into normal
  medical practice. This type of genetic testing
  isnt new.
• In 1961, the Guthrie test sampled a newborns
  blood for the buildup of amino acid
  phenylketonuria (PKU)
• Today tandem mass spectrometry used to ID
  metabolism errors in newborns

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Genetic Testing

• Then, the polymerase chain reaction is used to
  help amplify the mutations, making it easier to
  ID. Today the availability of testing for rare
  diseases is increasing.

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Polymerase Chain Reaction
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Types of Tests

• Carrier Screen
• Prenatal Test
• Prenatal Screen
• Newborn Test

• Diagnostic Test
• Predisposition Test
• Predictive Test

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Types of Tests

• In 2005, the U.S. government mandated testing for
  29 conditions that are treatable and recommended
  testing for an additional 5 conditions that are
  currently untreatable.

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Genetic Counseling

• Most medical professionals receive very limited
  training in the field of genetics.
• The role of genetic counseling is expanding
• Recent definition shared deliberation and
  decision making between the counselor and the
  client
• Reasons people seek counseling
• Prenatal diagnosis
• Disease in the family

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Genetic Counselors

• Sessions with a counselor begin with the
  families medical history being summarized in a
  pedigree, which includes knowledge of the risks
  of precurrence for other relatives
• From there, they discuss the condition, and try
  to determine which tests to take, or if assisted
  reproductive technology is needed
• Once the couple decides which tests are
  appropriate, the counselor must ask if the risks
  outweigh the benefits
• Often, communication can be hard-counselors must
  be sensitive and respectful, yet give their best
  opinion on what would be right for the clients

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Genetic Counselors

• There are only 2,200 genetic counselors in the US
  with a masters degree, and most practice in urban
  areas. Access to their services is limited.
• Other less-qualified professionals have been
  called in to fill their shoes
• As long genetic testing becomes more commonplace
  medical practice, and more is learned about
  genes, the need for genetic counselors will
  continue to rise

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Genetic Privacy

• Since results of genetic tests may have large
  impact on a persons life, they may want to keep
  such information private
• Doctors must weigh the risks and benefits of
  keeping this info confidential, if doing so may
  cause harm
• Duty to warn- Doctors must know when it is
  better judgment to inform someone of a patients
  genetic disease or the risks associated with it
• Court cases have brought this issue to the
  forefront
• Now, the AMA mandates a doctor may disclose info
  if
• Harm keeping quiet outweighs harm of breaching
  confidentiality
• Relatives at risk can be identified
• Failure to warn places the patient is at great
  risk

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Treating Genetic Disease

• Treatment has evolved in 3 phases
• Replacing missing proteins w/ donations
• Obtaining pure proteins w/ recombinant DNA
  technology
• Delivering replacement genes to correct the
  problem, also called GENE THERAPY

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Gene Therapy

• Treating the phenotype can be simple, like
  supplying a missing protein in a persons diet,
  or even using corrective eyewear
• However, altering genes directly will have a
  better effect than just treating symptoms

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Genetic Therapy

• Concerns
• Which cells to treat, and how?
• Is gene overexpression dangerous?
• Will the immune system attack the introduced
  cells?
• Does the targeted DNA sequence occur in other
  genes?
• Does the participant truly understand the risks?
• If effective, how will the recipients be selected
• Should rare or more common disorders be the focus
  of research and clinical trials?

• Requirements
• Knowledge of defect and how it causes symptoms
• An animal model
• Success in human cells growing in vitro
• No alternate therapies
• Safe experiments

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Gene Therapy

• First efforts focused on inherited disorders that
  researchers knew the most about
• With the increasing understand of human genes and
  their function, gene therapy is nowadays
  targeting more common illnesses
• 3 approaches
• Ex vivo-cells altered outside the body, then
  infused with corrected gene and returned to the
  body
• In situ-healthy gene plus DNA delivering it
  (the vector) are injected into a localized body
  part
• In vivo-vector introduced directly into the body

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Ex vivo illustration
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In vivo illustration
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Germline Vs. Somatic

• Germline (aka inheritable) gene therapy alters
  DNA of a gamete or fertilized ovum all alleles
  are changed, and passed on to offspring not used
  on humans
• Somatic gene therapy corrects only the cells an
  illness affects the cure isnt passed on to
  offspring, and no gametes are altered

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Gene Delivery

• Three ways
• Physical electroporation, microinjection,
  particle bombardment
• Chemical liposomes can enclose gene cargo and
  other lipids that carry DNA across the plasma
  membrane
• Biological Vector such as a viral genome used,
  as the viral gene is removed and corrective genes
  replace it.

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Viral genomes types and treatment

• Adeno-associated virus (AAV) sickle cell,
  Canavan disease
• Adeno virus (AV) cystic fibrosis, emphysema
• Herpes brain tumors
• Retroviruses HIV, cancer, Gaucher disease

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Sites for Gene Therapy

• May be applied directly to tissue affected, or
  into cells that can produce a needed protein and
  divide, such as stem cells and progenitor cells,
  because they divide well and can travel fast, and
  change the fate of daughter cells
• OR
• These may be targeted.

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Gene Therapy Sites

• Endothelium genetically altered endothelium can
  secrete a needed protein directly into the
  bloodstream
• Skin A skin graft can be genetically modified to
  secrete therapeutic proteins
• Muscles in Duchenne muscular dystrophy (DMD),
  the dystrophin gene can be cut smaller to deliver
  to cells so the muscles can function normally
• Liver delivering the gene that encodes for the
  LDL receptor, so more LDL can be produced to
  treat familial hypercholesterolemia (FH)

• Lungs several aerosols can be used to treat
  cystic fibrosis by replacing the defective gene.
  In AAT deficiency, levels of the enzyme elastase
  destroy lung tissue Increasing the amount of the
  AAT enzyme will help prevent this.
• Nerve tissue fibroblasts used to secrete nerve
  growth factors or make enzymes that produce
  neurotransmitters
• Cancer ½ of all gene therapies target cancer.
  Suicide gene therapy may be used, as the vector
  or gene is introduced which kills the cells.
  Also, vaccines can be used to mark tumor cells so
  the immune system can recognize them easier

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Suicide Gene Therapy
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Sickle Cell Disease

• Sickle cell disease is perhaps the most
  studied/researched inheritable disease
• Could turning on fetal hemoglobin cure sickle
  cell by replacing the mutant beta chains (sickle
  BCs) with normal gamma globin chains (fetal
  hemoglobin)?
• In adults, the gamma genes are normally silenced
  with methyl groups. A drug called hydroxyurea
  can remove these groups, exposing the gamme
  genes. With the increase of gamma globin
  molecules in the bloodstream, these bind to the
  mutant beta globins, which prevents some cells to
  take on sickle shape. This prolongs the time it
  takes for the beta chains to join, and RBCs are
  allowed to get into the lungs. Once cells pick up
  oxygen, sickling can no longer occur.

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Hydroxyureas Effect
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Gradual Success, but worth the wait

• Soon, gene therapy will be applied to all common
  disorders, not only rare diseases
• Because of success in the 1980s, huge
  expectations were held for the 90s.however, the
  progress has become painstakingly slow
• Not every treatment is a 100 cure some is only
  minimal physically
• Discoveries in the genome have revealed
  complexities that have yet to be worked around
• Discovery of RNA inheritance may complicate gene
  therapy
• Somatic vs. Germline
• Although minimal, there IS success
• The right vectors MUST be found for further
  progress

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Works Cited

• McGleenan, Tony. Human Gene Therapy and Slippery
  Slope Arguments. Journal of Medical Ethics 21(6)
  350-355, December 1995.
• Lysaught, M. Therese. Gene "Therapy" A Test Case
  for Research With Children. Genetics and Ethics
  An Interdisciplinary Study, 6th ed. St. Louis,
  Missouri Saint Louis University Press, 2004, pp.
  216-252.
• Zohar, Noam J. Prospects for Genetic Therapy
  -- Can a Person Benefit from Being Altered?.
  Bioethics 5(4) 275-288, October 1991.