Biomedical Engineering Reference
In-Depth Information
transduce non-dividing as well as dividing cells. The lentivirus preintegration
complex is able to pass the intact nuclear membrane, which allows it to integrate
into the host genome without cell division [
152
]. It was reported that animals can
be repeatedly infected with lentiviral vectors [
153
].
Adenoviruses are double-stranded DNA viruses with a diameter of approxi-
mately 110 nm. Adenoviruses infect both replicating and non-replicating cells,
have a relatively large genome, and are unable to integrate into the host genome
[
154
]. A number of serotypes has been used to create adenoviral vectors and
employed in 24.8 % of clinical trials till the end of March, 2008 [
155
]. These
vectors exhibit a broad range of liver tropism with serotype 5 as the most com-
monly used to date [
156
]. Adenoviral vector is the first proven gene carrier for the
treatment of cancer [
157
]. Because this virus is a natural human pathogen, pre-
existing immunity against adenovirus can cause severe allergic reaction and
inactivation of viral vectors [
158
]. The current strategy in avoiding these problems
is to use a serotype which the patients have no immunity against [
156
]. If the
immunogenic drawbacks can be overcome in the future, adenoviral vectors will
probably find a great diversity of clinical applications.
Adeno-associated virus (AAV) belongs to the Parvoviridae virus family and is
approximately 26 nm in diameter without envelope [
159
]. It requires a helper virus
for replication such as adenovirus. It is non-pathogenic and can infect quiescent
cells. AAV is currently classified into 12 serotypes, and the liver is known to be a
preferential target especially for AAV-8 [
160
]. It was reported that this virus can
insert its genome at a defined site on chromosome 19 termed AAVS1 with nearly
100 % certainty [
161
]. The site-directed integration is controlled by viral Rep
proteins [
162
], which are often deleted in recombinant AAV vectors in favor of
more space for the exogenous gene to be packaged into the tiny viral particle.
Cotransfection of plasmids coding for Rep protein was reported to restore capa-
bility of the site-directed integration and enable a long-term expression of the
transgene without inducing insertional mutagenesis [
163
]. Results from a number
of animal studies also indicate that AAV is less immunogenic when compared to
adenoviruses [
164
].
Preclinical Evaluation
Feasability of gene therapies has been demonstrated in a wide variety of animal
models. Long-Evans cinnamon rats are a model of Wilson disease and transfer of
the ATP7B gene to hepatocytes ameliorates both biochemical and histological
pathologies [
165
]. Transgene products released into blood circulation after suc-
cessful gene transfer into the hepatocytes corrected pathological manifestation
both inside and/or outside of the liver in glycogen storage diseases (type Ia, [
166
]
Ib [
167
] and II [
167
], mucopolysaccharidosis type I [
168
], IIIB [
169
] and VII
[
170
], hereditary tyrosinemia type I [
171
], UDP glucuronyltransferase deficiency
(Crigler-Najjar type I) [
172
], and hemophilia [
173
-
175
].
