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Molecular Basis for
Relationship between Genotype and Phenotype
genotype
DNA
DNA sequence
transcription
RNA
translation
protein
function
phenotype
organism
amino acid
sequence
Gene Therapy
Germ-line Therapy vs Somatic Therapy
Gene Therapy in Mammals
Human Gene Therapy

Approaches
to treatment
of diseases
 DNA transfer
into afflicted
individual
1990 : First Clinical Trial
Severe Combined Immunodeficiency
(SCID)
- defective adenosine deaminase
(ADA) gene.
- afflicted patients express no
functional T or B lymphocytes.
- “Bubble Boy Disease”
Delivery Approaches to Somatic Therapy
• Direct Administration:
Introduction of normal gene using a virus
retrovirus
adenovirus
• Indirect Administration:
Reintroduction of cells that have been
made transgenic
Criteria for Gene Therapy:
Candidacy of a Disease for Consideration
1. Mendelian inheritance
2. One gene product for the gene
3. Knowledge of function of gene product
4. Availability of normal gene sequence
5. Localized symptoms for the disease
6. Availability of delivery system
~ 25,000 genes in humans are potential candidates for gene therapy.
Candidates
for
Gene Therapy
?
~ 25,000 genes in humans are potential candidates for gene therapy.
Cystic Fibrosis
Disease is usually fatal.
Lungs, other organs are clogged with mucus.
repeated bouts of pneumonia
heart stressed by decreased lung capacity
delivery failure of pancreatic enzymes
Life expectancy of 20-25 years
~1 of 29 Caucasians are carriers
~1 of 1600 Caucasians are affected
~30,000 Americans are affected
Cystic Fibrosis
•
Caused by recessive mutation (chromosome 7)
•
Failure to pump Cl- ions across cell membrane
•
Missing Cl- ion channel protein (cystic fibrosis
transmembrane protein or CFTR)
•
Normal gene sequence available (cloned in 1989)
•
Normal gene 250 kb in size
•
Transcript of 6 kb in size
•
Gene product of 1480 amino acids in length
•
Over 1500 mutations documented
Cystic Fibrosis as Candidate for Gene Therapy
1. Recessive gene on chromosome 7.
2. CFTR is the gene product.
3. CFTR is an ion channel protein.
4. Normal gene sequence has been cloned.
5. Symptoms are localized to specific organs.
6. Adenovirus (cold virus) can be used to
deliver normal sequence to lung cells.
Human DNA Information:
Ethical Concerns
Who should have access
to your DNA information?