Genetic Disorders
and
Gene Therapy
Overview of Lesson
• Genetic diseases
– Chromosomal
– Single gene
• Gene Therapy
– What is it?
– How is it done?
Chromosomal Diseases
• Gametes have abnormal
chromosome numbers and
mutations
• Offspring inherit extra
chromosome or are missing a
chromosome
• Caused by problems with
meiosis
Nondisjunction of chromosomes during meiosis
Based on: Brooks/Cole – Thomson Learning
Characteristics of a child with Down
Syndrome
-wide, rounded face
-Lower cognitive ability
-enlarged tongue
Normal female
karyotype with 46
chromosomes
Based on: Mader, S., Inquiry Into Life, McGraw-Hill
-equal length fingers
-webbed neck
Down syndrome
karyotype with an extra
chromosome 21
Overview of Lesson
• Genetic diseases
– Chromosomal
– Single gene
• Gene Therapy
– Process
– Vectors
Important Points about Inheritance
•Genes have different forms, called
alleles
•Each trait is controlled by effects of
two alleles
•Some alleles are:
• dominant/recessive
• other alleles are co-dominant
Hairline Traits
•Allele for Widow’s Peak
is dominant
•A person with WW or Ww
will have Widow’s Peak
•Allele for Straight Hairline
is recessive
•A person with ww will have
a Straight Hairline
http://images.google.com/
Genotype vs. Phenotype
•Genotype refers to the alleles
•Phenotype refers to the appearance
Example: Genotype - Phenotype
WW - person has a widow’s peak
Ww - person has a widow’s peak
ww - person has a straight hair line
Genetics & Human Diseases
• About 4,000 human diseases are
thought to be inherited.
• Scientists are making good
progress figuring out where
genes are located on
chromosomes.
• Genetic diseases are caused
by mutations, or incorrect
sequences, in the normal form
of the gene.
Huntington’s Disease
• Results in a loss of muscle
control and mental function.
• The symptoms usually do not
appear until after 30 years old.
• 1 in 10,000 people.
Caused by a dominant
allele
Cystic Fibrosis
Mucus in bronchi is thick,
interfering with lung function
1 in 25 are carriers
One of the first disorders to be
actively studied for gene therapy.
Most lethal autosomal recessive
disorder in U.S.
Sickle Cell Disease- recessive allele
•Red blood cells are sickle shaped, issues with circulation
causing anemia and pain
Based on: Harvard Family Health Guide, 1999
Sickle cell disease
(sickle cell anemia)
• Codominant disorder found in
African Americans.
– 1 in 400 African Americans
• Can be fatal.
• Possible cure: bone-marrow
transplants
• The sickle cell trait can prevent
Malaria
Hemophilia
• A disorder in which
a person’s blood
does not clot
properly.
• It is a recessive sexlinked, Xchromosome
disorder.
“Royalty Disease” • 1 in 10,000 males
born are afflicted.
Adenoside Deaminase (ADA) Deficiency
ADA-deficient persons are affected by
severe immunodeficiency, with recurrent
infections that might be life-threatening.
First disease approved for gene therapy.
Autosomal recessive disorder.
The drug exists but is very
expensive, needs to be injected
in vein for life.
Overview of Lesson
• Genetic diseases
– Chromosomal
– Single gene
• Gene Therapy
– What is it?
– How is it done?
What is Gene Therapy?
• Gene therapy is a
treatment or cure for
disorders caused by
mutated genes.
• It involves adding a
normally functioning
copy of the gene(s) to
enough affected cells to
restore normal function.
What is Gene Therapy
• Germline gene therapy would be the
permanent transfer of a gene into
sperm or egg cells.
– Future generations would be “cured”.
• Somatic cell (body cell) gene therapy
is ideally only the transfer of genes
to the affected cells.
Gene Therapy Successes
• Although no gene therapies have
been approved by the FDA for sale,
some diseases have been
experimentally successful:
– Melanoma (skin cancer)
– Severe Combined Immunodeficiencies
– Hereditary Blindness
– Sickle Cell Anemia
How is it done?
Viral Vector Carrying Healthy Gene
Cell with mutated
gene(s)
Vector inserts
healthy gene into
cell
New gene in the
cell along with
original genes
Functional proteins are created from the therapeutic gene
causing the cell to return to a
state.
Gene Therapy
To design and carry out a gene therapy
treatment, a researcher must:
1. Identify the gene(s) responsible for the
disorder.
2. Make copies of the normal gene.
3. Insert the copies into vectors.
4. “Infect” the affected cells with the vectors.
5. Activate the gene so that transcription and
translation take place.
Viruses as Vectors
• Replicate by inserting their DNA into
a host cell
• Gene therapy can use this to insert
genes that encode for a desired
protein to create the desired trait
• Four different types
– Adenovirus
– Adeno-Associated Virus (AAV)
– Retrovirus
– Herpes Simplex Virus (HSV)
Vector Advantages and Disadvantages
• Adenovirus
+ Infects many cell types
− Does not integrate into host genome and can be lost.
• Retrovirus
+ Integrates into host genome and cannot be lost
− Integrates into host genome and can cause cancer
• Adeno-Associated Virus (AAV)
+ Integrates into host genome and cannot be lost
− Difficult to work with.
• Herpes Simplex Virus (HSV)
+ DNA stays in nucleus without integrating into host
genome.
− Only infects cells of the nervous system.
Gene Therapy
Disappointments
• In 1999 a boy died due to an
immune response to an adenovirus
gene therapy vector.
• Four children have developed
cancer due to a retrovirus gene
therapy vector
My Research: Building a better Vector
Adenovirus
shell delivers
genes
HSV-like virus
protein tethers DNA
to chromosome to
keep genes in cell
without integration
Your Goals:
• Learn more about gene therapy by
completing a becoming a SPACE
DOCTOR!
• Gene Therapy Vector Engineering
Project.
– First groups to complete the Space Doctor
activity gets to chose from the genetic
diseases we talked about today.
– Use what you have learned and the Vector
Toolbox to choose the best vector for treating
the disease.
Tomorrow
• Learn about the techniques used to
genetically engineer gene therapy
vectors.
• Gene Therapy Vector Engineering
Project.
– Use paper models to simulate the
process of engineering your gene
therapy vector.