Biomedical Engineering Reference
In-Depth Information
particles) administered directly into the liver through the portal vein. These results
should not provoke investigators to throw out the adenoviral vector gene therapy, but
they do indicate that further modification of the technology is required, and great cau-
tion should be used when administering vector directly into the liver. Some other appli-
cations of adenoviral vectors for gene therapy are as follows:
1. Overexpression of specific genes by adenoviral vector is used for therapeutic purposes,
such as the overexpression of metalloproteases for the treatment of cirrhosis.
2. In some situations, CN1 or LDL receptor deficiency (familial hypercholesterolemia), the
missing gene product was expressed by Ad vector in the liver for appropriate metabolic
effect [51] .
3. The catalytic subunit of the apolipoprotein B mRNA-editing enzyme (APOBEC-1) could
be expressed ectopically in the liver by Ad vector to switch the hepatic apolipoprotein pro-
duction from apo B100 to apo B48, thereby reducing the production of LDLs, which are
normally expressed in the intestinal epithelial cells [52] .
4. Expression of PDX, a homeobox protein that is responsible for pancreatic differentiation in
liver, has shown secretion of insulin from hepatocytes [53] .
5. In liver cancers, loss of p53 function is one of the most frequent genetic alterations. Both
replication-incompetent (rAd.p53, or SCH58500) and replication-selective (dl1520, or
Onyx-015) adenoviral vectors are being developed for the treatment of p53-deficient can-
cers [54,55] .
6. For development of new therapeutic agents for human hepatocellular carcinoma, the high-
affinity and high-stability antibodies for targeting tumor-specific antigens, adenoviral vec-
tors expressing monoclonal antibody (MAb) AF-20 raised against a human hepatoma cell
line, and high-affinity single-chain MAb fragments (scFv) have been generated [56] .
7. Nucleic acids may be used to inhibit the expression of toxic proteins, such as viral proteins
or mutant  1 -antitrypsin [57] .
5.2.6.2 Immunologic Modifications of Ad For Liver-Targeted Gene Therapy
Limited clinical application of adenovectors is due to cellular and humoral immune
responses to adenoviral proteins. Adenoviral-specific cytotoxic lymphocytes attack
the host cells, damage the liver, and cause rapid loss of the transgene after secondary
gene transfer [58,59] . The helper-dependent adenovectors, in which all viral genes
are deleted, may also retain immunogenicity because of the packaging cells that pro-
vide the viral proteins in trans . Even if these vectors express transgenes for a longer
duration than the first-generation adenoviral vectors, secondary or tertiary admin-
istration fails to transfer the transgene. In humans, antibodies often exist from pre-
vious infections by adenoviruses. These native antibodies readily produce humoral
and cell-mediated immunity against the viral antigenes after initial injection of the
recombinant adenoviral vectors. Neutralizing these antibodies blocks gene transfer
by the recombinant vectors.
CTLA4-Ig, a soluble inhibitory protein, inhibits B7-CD28 costimulation, which
leads to prevention of an effective immune response. The adenoviral vector does not
prevent antibody formation by injecting CTLA4-Ig alone at the time of administra-
tion. However, coexpression of CTLA4-Ig with the target transgene permits multiple
administration of the recombinant Ad [60] .
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