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Gene therapy can be targeted to somatic ... In germline gene therapy, the parent's egg or ... Attempting gene therapy with out knowing how everything works ... – PowerPoint PPT presentation

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It is an approach to treat, cure, or ultimately
prevent disease by changing the expression of a
persons genes. Gene therapy is mostly
experimental, and most human trials are only in
the research stages.
Gene therapy can be targeted to somatic or germ
In somatic gene therapy the recipients genome is
changed, but the change is not passed along to
the next generation. In germline gene therapy,
the parents egg or sperm cells are changed with
the objective of passing on the changes to the
offspring. Its not currently used in humans
or larger animals.
Hurdles in gene therapy.
  • Gene delivery tool. The new gene/s are inserted
    into the body
  • via vehicles called vectors (gene carriers) which
  • therapeutic genes to the patients cells.
  • The most common vectors are viruses. Scientists
    are trying to
  • manipulate the viral genome to remove the
    disease-causing genes
  • and introduce therapeutic genes. Viruses
    introduce potential other
  • problems in the body, such as toxicity, immune
    and inflammatory
  • responses, and gene control and targeting
  • Alternatives being considered are complexes of
    DNA with lipids and
  • proteins.

Researchers are also experimenting with
introducing a 47th artificial chromosome to the
body. It would exist autonomously along side of
the other 46, not affecting their workings or
causing any mutations. It would be a large
vector capable of carrying substantial amounts
of genetic information and the bodys
immune system would not attack it.
2. Understanding gene function
Of the estimated 30-50,000 genes, we know the
function of a very few. Attempting gene therapy
with out knowing how everything works could
address only some of the genes implicated in
particular diseases. Likewise, genes may have
more than one function.
Example. Sickle cell anemia Its caused by a
mutation in the gene for hemoglobin. The disease
manifests itself only when two copies of the
mutated gene is inherited. People with only one
copy of the mutated gene not only are healthy,
but they are more resistant to malaria, which is
endemic in some areas of Africa. The mutation
originated several thousands of years ago in
parts of Africa, the Mediterranean basin, Middle
East and India. Because of the survival
advantage the mutation was passed along through
Though, as yet, there is no cure for SCA, a
combination of fluids, painkillers, antibiotics
and transfusions are used to treat symptoms and
complications. Hydroxyurea, an antitumor drug,
has been shown to be effective in preventing
painful crises. Hydroxyurea induces the
formation of fetal Hb (HbF),  a Hb normally found
in the fetus or newborn  which, when present in
individuals with SCA, prevents sickling. A
mouse model of SCA has been developed and is
being used to evaluate the effectiveness of
potential new therapies for SCA.
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How would you design a gene therapy targeting
the HBB gene?
3. Multigene disorders. Most genetic disorders
involve more than one gene, so inheritance of
one particular gene does not mean that you have
100 chances of developing that disorder. The
particular environment (diet, smoking habits,
exercise, exposure) also has a big impact on
disease development. 4. High cost associated
with developing this technology, and regulations
associated with human experimentation.
Genetic therapy .more in depth The goal is
usually to supply cells with healthy copies
of missing or altered genes. Its an alternative
to drugs. It can also be used as a way to change
how a cell functions by stimulating the immune
system cells to attack cancer cells or by
introducing resistance to some viruses (e.g. HIV)
Viruses are used as vectors to introduce the
genetic material inside the bodies. These
viruses are inactivated, they are not able to
reproduce. Adenoviruses Herpes viruses
DNA tumor viruses Retroviruses
RNA tumor viruses
Retroviruses are used for their ability to
transform their RNA into DNA, which then becomes
part of the DNA of the host cell. Retroviruses
can be used also to deliver genes that makes
cancer cells sensitive to certain drugs.
What possible problems do you see?
Gene therapy step by step 1. Bone marrow from
the patient is removed and grown in
the laboratory. 2. The cells are exposed in
culture to the virus carrying the desired
gene. 3.After infection, and integration of the
desired gene in the cells DNA, the cells are
returned to the patient by injection into a vein.
This technique is called ex vivo because the
gene is transferred to the cells while they are
outside the patients body. In the in vivo
technique, the gene is transferred to cells
inside the patients body by using liposomes
(fatty particles).
First disease approved for gene therapy treatment
was adenosine deaminase (ADA) deficiency. ADA is
a rare genetic disease. Normal ADA gene produces
an enzyme called adenosine deaminase essential
for effective immune system function.
ADA-deficient persons do not produce the enzyme
and are affected by severe immunodeficiency, with
recurrent infections that might be
life-threatening. The drug exists but is very
expensive, needs to be injected in vein for life.
  • Why ADA
  • The disease is caused by a defect in a single
  • The gene is regulated in a simple, always on
  • unlike many genes whose regulation is complex.
  • 3. The amount of ADA present does not need to be
  • precisely. Even small amounts are beneficial, and
    large amounts
  • are well tolerated.
  • First clinical trial was conducted in 1990 on two
  • The treatment had to be repeated several times in
    three years.
  • Now the children have to take a smaller dose of
    the drug to keep
  • the disease under control.

Risks associated with current gene
therapy Viruses can infect more than one type of
cells. Viral vectors may alter more than the
intended cells. Or the new gene might be
inserted into the wrong location in the DNA,
causing cancer or other damage. When DNA is
injected directly into a tumor there is a chance
that some DNA could be introduced into germ
cells, producing inheritable changes. The gene
might be over-expressed (toxicity) the viral
vector could cause inflammation or immune
reaction the virus could be transmitted to other
individuals or the environment.
Gene therapy in cancer treatment Objectives
improve the bodys natural ability to fight the
disease or make the cancer cells more sensitive
to other kinds of treatment. Some techniques
under study include -Substitution of a working
copy of a gene for an inactive or defective gene
(e.g. restore the ability of p53 to suppress the
development of cancer cells). -Injection of
cancer cells with a gene that makes them more
sensitive to treatment with anticancer
drugs. -Introduction of the multidrug resistant
gene (MDR) into stem cells to make them more
resistant to the side effects of the anticancer
Major challenges 1.Scientists need better ways
to deliver genes to the body, more target
specific with higher rate of DNA
integration. 2.Ability to deliver genes
consistently to a precise DNA location and
ensure that the transplanted gene is controlled
by the bodys physiologic signals
Social and ethical issues Potential for altering
germ cells that are passed through
generations (alter human capabilities or features
by genetic manipulation). Germ-line therapy is
not currently approved by NIH. -Luxury available
to a restricted group -Definition of normal and
exclusion of average types -Eugenics
improvement of genetic qualities through
selective breeding. To address these concern
the ELSI Program was established in
1990. Ethical, Legal, and Social Implications.
Drugs development Properties Ethics Economics Exa
Pathogens Bacteria Fungi Viruses Cancer
  • Properties of a good drug
  • Safe
  • Effective
  • Stable
  • Synthetically feasible to produce
  • Soluble
  • novel

  • And 2. Efficacy versus acceptable level of side
  • 3. Necessary for potency
  • 4. Structure in vitro is not always the same as
    in vivo
  • 5. Rocks in your bladder
  • 6. Patent

Once you have the drug you have to go
through -in vitro testing -animal testing NIH
Phase I Phase II clinical
trials Phase III market
In vitro testing would it work Animal testing
gives an idea about safety and effectiveness
Phase I drug to healthy volunteers to observe
side effects. Regulations are in place about
where you have to run this If you want to sell
the drug. Phase II Small number of people with
the condition (10-50) Check out safety and
dosage. Phase III Large double blind study
500-1000 people Placebo and no
one knows who is in which group.
2 of the drugs tested make the market.
Drug design Drugs have to be as specific as
possible. Ideally it should target the infected
cell or cancer cell, only. Smart
drug Example Drug for cancer or viral infected
cells has to affect DNA synthesis. AZT chain
terminator (nitrogen group) Acyclovir similar