Biomedical Engineering Reference
In-Depth Information
Table 14.3
Some characteristic advantages and disadvantages of adenoviruses as potential vectors for
gene therapy. Refer to text for further details
Advantages
Disadvantages
Adenoviruses are capable of gene transfer to non-
dividing cells
Adenoviruses are highly immunogenic in man
They are easy to propagate in large quantities
The duration of expression of transferred genes can
vary, and is usually transient
High levels of gene expression are usually recorded
Infection of permissive cells with wild-type adenovirus
usually results in cell lysis
They are relatively stable viruses
Adenoviruses display a broad selectivity in the cell
types they can infect
observed expression of large quantities of the desired gene products. However, the failure of the
adenoviral-based DNA to integrate into the host cell generally means that its survival and, hence,
the duration of gene expression, is limited. Adenovirus-based vectors, carrying various marker
genes (i.e. a gene whose expression product is easily detected), have been administered to ani-
mals. Marker gene expression has been subsequently noted in various tissues, including heart,
liver, muscle, bone marrow, central nervous system and endothelial cells. Duration of marker gene
expression ranged from 2-3 weeks to several months.
Whereas short-term, high-level gene expression may be appropriate for some gene therapy applica-
tions, it would be of less use for the treatment of, for example, genetic diseases, where long-term gene
expression would be required. This could be achieved, in theory, by repeat administration of the ad-
enoviral vector. However, adenoviruses prompt a strong immune response, which limits the effi cacy
of repeat administration. Indeed, the gene therapy trial death in 1999, as mentioned previously, was
apparently caused by a severe and unexpected infl ammatory reaction to the adenoviral vector used.
Additional viruses that may prove of some use as future viral vectors include adeno-associated
virus and herpes virus. Adeno-associated virus is a very small, single-stranded DNA virus: its
genome consists of only two genes. It does not have the ability to replicate autonomously and can
do so only in the presence of a co-infecting adenovirus (or other selected viruses).
Although it is found in the human population, it does not appear to be associated with any known
diseases. Not surprisingly, only relatively small genes can be introduced into adeno-associated
viral vector systems. Such systems, however, do provide a mechanism of gene transfer into non-
dividing cells. It also seems to facilitate long-term expression of the transferred genetic material.
In contrast to adenoviruses, nucleic acid transferred by adeno-associated viruses appears to be
integrated into the recipient cell genome.
The herpes simplex virus represents another potential vector system that is receiving increased
attention. Because herpes simplex virus is a neurotrophic virus, it may prove to be particularly
useful in delivering genes to neurons of the peripheral and central nervous system. Upon infection,
herpes simplex virus usually remains latent in non-dividing neurons, with its genome remaining
in an unintegrated form. Thus far, it has proven diffi cult to generate a replication-incompetent, but
yet viable, herpes simplex particle. Moreover, some of the replication-incompetent viruses gener-
ated still retain an ability to damage/destroy the cells they infect. Although herpes-based vector
systems one day may prove useful in gene therapy, suitable and safe vector variants of herpes
simplex virus must fi rst be generated and tested.
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