Genetic Disease

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Genetic Disease
Duchennes Muscular Dystrophy Pedigree
Genetics Home Reference
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• A genetic disorder is a disease caused by
  abnormalities in an individuals genetic material
  (genome).
• There are four different types of genetic
  disorders
• (1) single-gene,
• (2) multifactorial,
• (3) chromosomal, and
• (4) mitochondrial.

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Single Gene Mutations

• Changes or mutations that occur in the DNA
  sequence of one gene.
• More than 6,000 single-gene disorders (about 1
  out of every 200 births) are known.
• e.g. cystic fibrosis
• sickle cell anemia
• Marfan syndrome
• Huntingtons disease

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Multifactorial

• Combination of environmental factors and
  mutations in multiple genes.
• e.g. heart disease,
• high blood pressure
• Alzheimers disease
• arthritis
• diabetes
• cancer
• obesity

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Chromosomal

• Abnormalities in chromosome structure such as
  missing or extra copies or gross breaks and
  rejoinings (translocations).
• e.g. Down syndrome
• Turner syndrome

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Mitochondrial

• Rare type of genetic disorder is caused by
  mutations in the non-chromosomal DNA of
  mitochondria.

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Genetic Testing

• 1. Direct examination of the DNA molecule
  itself.
• 2. Biochemical tests for gene products such as
  enzymes and other proteins
• 3. Microscopic examination of stained or
  fluorescent chromosomes.

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Genetic Screening

• Carrier screening
• Preimplantation genetic diagnosis (PGD)
• Prenatal diagnostic testing
• Newborn screening
• Presymptomatic testing for predicting adult-onset
  disorders such as Huntington's disease cancers
  and Alzheimer's disease
• Forensic/identity testing

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Is genetic testing regulated?

• Currently in the United States, no regulations
  are in place for evaluating the accuracy and
  reliability of genetic testing

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Does insurance cover genetic testing?

• Usually insurance companies do not cover genetic
  tests
• Cost between 200 and 3000
• Would the patient want the
• insurance company to have
• this information?

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Societal Concerns Arising from the New Genetics

• Fairness in the use of genetic information
• Privacy and confidentiality
• Psychological impact and stigmatization
• Reproductive issues
• Clinical issues
• Uncertainties
• Conceptual and philosophical
• implications
• Health and environmental issues
• Commercialization of products

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Gene Therapy

• Gene therapy is a technique for correcting
  defective genes responsible for disease
  development.

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• A normal gene may be inserted into a
  nonspecific location within the genome to replace
  a nonfunctional gene. This approach is most
  common.

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• An abnormal gene could be swapped for a normal
  gene through homologous recombination.

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• The abnormal gene could be repaired through
  selective reverse mutation, which returns the
  gene to its normal function.

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• The regulation (the degree to which a gene is
  turned on or off) of a particular gene could be
  altered.

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Viral Vectors

• Viruses have evolved a way to deliver DNA to
  human cells and are used in gene therapy.
• Retroviruses make DNA from RNA, integrates into
  host genome
• Adenoviruses cause respiratory, intestinal and
  eye infections
• Adeno-associated viruses insert their DNA into
  specific site on chromosome 19.
• Herpes simplex viruses infect neurons, cause
  cold sores.

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Gene Therapy Using An Adenovirus Vector.
A new gene is inserted into an adenovirus vector,
which is used to introduce the modified DNA into
a human cell. If the treatment is successful, the
new gene will make a functional protein.
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Severe Combined Immunodeficiency Disorder - SCID

• A broken gene eliminates the production of an
  enzyme essential for the development of a normal
  immune system. Scientists isolated the normal
  copy of the gene and packaged it into a vector.

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David Vetter the Bubble Boy- died at age 12 of
SCIDs
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French researchers reported dramatic results in
treating severe combined immune deficiency
(SCID), the disorder suffered by David
Vetter. Unfortunately, some of the children
developed leukemia. Gene therapy may cure
bubble boy disease Treatment seems to have
cured 8 of 10 kids who had rare, deadly condition
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What factors have kept gene therapy from becoming
an effective treatment for genetic disease?

• Short-lived nature of gene therapy
• Immune response
• Problems with viral vectors
• Multigene disorders

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Ashanti de Silva
Ashanti was born with adenosine deaminase
deficiency (ADA) which affects the immune system
and results in SCIDS. In 1990, at four years of
age Ashanti became the first gene therapy
patient. Her therapy was a success and she still
shows no side effects (2005)
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• Before the advent of gene therapy, there were
  two ways to treat ADA-SCID.
• 1. Regular injections with the ADA enzyme,
  administered as a mixture with polyethylene
  glycol (PEG) to increase its stability.
• 2. A bone marrow transplant from a compatible
  donor.

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• ADA deficiency was an ideal target for the
  first gene therapy trials for a number of
  reasons
• 1. the pathological effects of the disease are
  reversible
• 2. the disease results from the loss of function
  of a single gene
• 3. ADA levels vary widely in the normal
  population so tight control of the introduced
  gene is not important
• 4. the ADA gene is very small and easy to
  manipulate in the laboratory
• 5. the target cells for the therapy are
  lymphocytes, which are accessible, easy to
  culture and easy to put back into the body of the
  patient
• 6. the alternative treatments are expensive
  and/or hazardous.

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Jesse Gelsinger
Jesse had the rare fatal liver disorder,
ornithine transcarbamylase deficiency (OTCD) and
participated in a 1999 gene therapy trial at the
University of Pennsylvania. He died of
complications from an inflammatory response
shortly after receiving a dose of experimental
adenovirus vector. His death halted all gene
therapy trials in the United States for a time.
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Rhys Evans
A boy who had no immunity against infection
(SCIDS), has been brought back from the brink of
death and turned into a normal boisterous toddler
after the first successful application of gene
therapy in Britain, Rhys Evans was born in
September 2000 and soon lived as a "bubble baby",
kept alive on a ventilator, after repeated
infections made him so skeletal that he was too
weak to lift his head. He almost died last year
of pneumonia. But today, after gene therapy at
Gt Ormond Street Hospital in London, Rhys's
parents describe him as mischievous and bouncy.
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Current Research

• Gene therapy for Inherited Blindness
• Gene Therapy Safe for Regeneration of Gum Tissue

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What are some recent developments in gene therapy
research?

• Undercover genes slip into the brain
• Gene Therapy May Switch off Huntingtons
• Subtle Gene Therapy Tackles Blood Disorder
• Miracle Gene Therapy Trial Halted
• DNA Nanoballs Boost Gene Therapy