Biomedical Engineering Reference
In-Depth Information
or by bone marrow transplantation are low (\0.01 %), unless those bone marrow-
derived hepatocytes have a selective growth advantage [
141
-
143
]. Furthermore, in
most of the cases, fusion with host hepatocytes rather than transdifferentiation of
extrahepatic cells, has been described as the underlying mechanism [
144
-
147
].
So far no convincing evidence has yet been provided in animal models that stem
cells including HSC, MSC, iPS, or cells derived from cord blood or the amnion can
generate therapeutically significant numbers of hepatocytes for the correction of
hereditary metabolic liver diseases. Consequently, no credible data on the use of stem
cells in patients with hereditary liver disease have been published.
10.5.3.3 Gene Therapy
The liver is involved in the synthesis of serum proteins, regulation of metabolism,
and maintenance of homeostasis and thus provides a variety of opportunities for
gene therapeutic corrections. Gene therapy is the treatment of an inherited or
acquired disease through the manipulation of a patients' genetic status or sequence
in selected cells by introducing various types of genetic materials, such as virally
bound nucleic acids, plasmid DNAs, antisense oligonucleotides, and short inter-
ference RNAs. Both viral and non-viral methods have been developed for effective
gene delivery. Currently, only viral vectors have transduction efficacies needed for
liver-based gene therapy of inherited metabolic diseases in humans.
Viral Vectors
Viral gene delivery employs replication deficient viruses as a carrier to bring genetic
materials into cells through their natural infection mechanism. Viral vectors are
created using molecular biological techniques by which portion of the viral genome
is replaced with a gene of interest. Major drawbacks of viral vectors are their genetic
and immunologic toxicities, which are mainly associated with an arbitrary recom-
bination with genomic DNA of the target cells and acute immune stimulation,
respectively. Because adult humans have already developed immunity against sev-
eral types of viruses from which viral vectors are developed, an exposure of the viral
vectors to patients often results in strong immunological reaction, and consequently
disables efficient gene delivery and long-term gene expression.
Viral vectors frequently used in gene therapy studies are derived from retro-
virus, adenovirus, and adeno-associated virus. Retroviruses, enveloped RNA
viruses with a particle size of approximately 100 nm, only infect dividing cells and
are capable of integrating reverse transcribed DNA into the host genome at an
unpredictable location [
148
]. Viral integration has led to leukemia development as
revealed by recent gene therapy trial on X-linked SCID [
149
]. The requirement of
hepatectomy (*70 %) to stimulate hepatic proliferation is generally considered as
a drawback for retrovirus-mediated gene delivery to the liver [
150
,
151
]. Len-
tiviruses, a subclass of retroviruses including human immunodeficiency virus, can
