01. Gene therapy Boulikas.pdf - Gene therapy & Molecular Biology

Boulikas: An overview on gene therapy
Table 6. In vivo somatic gene transfer strategies to animal models
Gene target
or delivered
HSV TK and
ganciclovir
Prostaglandi
n G/H
synthase
Ornithine
transcarbam
ylase (OTC)
α1antitrypsin
α1antitrypsin
α1antitrypsin
(AT, human)
Human
disease
hepatocellular
carcinoma
acute lung
injury
OTCdeficiency
α1-antitrypsindeficiency
in
lung
α1-antitrypsindeficiency
in
liver
acute and
chronic lung
diseases.
CFTR Cystic fibrosis
(CF)
CFTR
(cystic
fibrosis
transmembra
ne
conductance
regulator)
Cystic fibrosis
(CF)
CFTR Cystic fibrosis
(CF)
90
the number of rotations/min for more
than 6 months
Method Animal model, objective, and method Results Reference
AAV
mice
Cat lipid
rabbit
Adenovi
rus
Adenovi
rus
Cat lipid
mice
To preferentially kill hepatocellular
carcinoma cells by the suicadal gene
HSV TK (driven by the α-fetal protein
(AFP) enhancer and albumin promoter)
with ganciclovir
Rabbits intravenously transfected with
the PGH synthase gene
iv injection of recombinant adenovirus
to spf-ash mice (OTC-deficient)
The adenovirus major late promoter
was linked to a human α1-antitrypsin
gene for its transfer to lung epithelia of
cotton rat respiratory pathway
Protect connective tissue from the lytic
action of the leukocyte neutrophil
elastase; plasmid was encapsulated into
negatively-charged liposomes
containing phoshpatidylcholine
Cat lipid Aerosol and intravenous transfection to
lungs of rabbits
Adenovi
rus
Selective killing of AFP-positive
cells in culture; transgenic mice were
established by injection of AAV
ITRs, neoR , and HSV TK genes as a
linear DNA fragment; HSV TK was
expressed predominantly in adult
liver.
Increased plasma levels of
prostacyclin and PGE2; protection of
lungs in rabbits against endotoxininduced
inflammation, pulmonary
edema, release of thromboxane B2,
and pulmonary hypertension
Correction of enzyme deficiency in
OTC-deficient mice for over 1 year.
Both in vitro and in vivo infections
have shown production and secretion
of α1-antitrypsin by the lung cells for
over 1 week
Small liposomes were much more
effective in delivering the α1antitrypsin
gene to mouse
hepatocytes in vivo.
Human α1AT mRNA and protein
were detected for at least 7 days;
immunohistochemical staining
showed α1AT protein in the
pulmonary endothelium following
intravenous administration, in
alveolar epithelial cells following
aerosol administration, and in the
airway epithelium by either route
To alleviate the symptoms of CF Expression of CFTR after
intratracheal instillation into lungs of
cotton rats; expression between days
2-10
Cat lipid To express the normal CFTR gene in
lungs of Edinburgh insertional mutant
mouse (cf/cf) after delivering CFTR
cDNA-liposome complexes into the
airways by nebulization.
Lipofect
in
CFTR CF Lipofect
in
CFTR
cDNA
(human)
Cystic fibrosis
(CF)
To express the human CFTR gene in
lungs in CFTR-deficient transgenic
mice by tracheal instillation of
lipofectin-plasmid
Transduction of airway epithelial cells
in normal mice by intratracheal
instillation of a plasmid carrying the
CFTR gene under control of the Rous
sarcoma virus promoter
AAV Intratracheal instillation into neonatal
New Zealand white rabbits
Full restoration of cAMP related
chloride responses in some animals;
human CFTR cDNA expression in
the same tissues
Successful transfer of the CFTR gene
to epithelia and to alveoli deep in the
lung leading to correction of the ion
conductance defects found in the
trachea of transgenic mice
Airway epithelial cells were the
major target and site of expression of
CFTR
Epithelial expression of the human
CFTR fusion protein was detected
using antisera to both the human
Su et al, 1996
Conary et al 1994
Stratford-Perricaudet et al,
1990
Rosenfeld et al, 1991
Aliño et al, 1996
Canonico et al, 1994
Rosenfeld et al, 1992
Alton et al, 1993
Hyde et al, 1993.
Yoshimura et al, 1992
Rubenstein et al, 1997