Biology Reference
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control of vector genome regulation, in order to achieve stable and
physiological transgene expression in the required cells. For the
fi rst time, however, a defective recombinant vector (NP2) express-
ing preproencephalin has recently moved into a clinical trial to treat
pain due to malignancies [
41
]. There is no doubt that this is a very
signifi cant step that will generate important information on the
toxicity, safety, and behavior of the recombinant vectors, as well as
on the regulation of transgenic expression in humans. This will
certainly lead to new insights that will allow the improvement of
these vectors and will accelerate their use in the frame of other
neurological diseases.
Due to their very large transgenic capacity, amplicons are one
of the most interesting, versatile, powerful, and promising gene
transfer platforms, and these vectors have been used in several
experimental gene therapy settings of neurologic disorders, as well
as in basic research in neuroscience, as a new and powerful tool for
modifying gene expression. However, and in spite of several recent
technological developments, regarding the ability to produce non-
toxic helper-free vector stocks [
28
,
29
], to deliver very large trans-
genic sequences [
117
,
118
,
120
,
121
], and to maintain the vector
genome in proliferating cells [
208
-
210
], these vectors have not yet
moved to the clinics.
The limitations of the amplicon system that should be resolved
before these vectors could be safely and effi ciently applied to human
beings in gene therapy protocols are of different orders. The produc-
tion and purifi cation procedures of amplicon vectors need to be, and
actually can be, further improved. We still do not completely under-
stand the factors that affect control of gene expression, which can
result in the silencing of the transgenic cassette delivered by ampli-
cons. The systems that have been designed to avoid dilution of the
transgenic cassettes in proliferating cells are still imperfect and can
certainly be optimized. Several aspects of the biology of amplicons,
related in particular to the cellular and host responses against infec-
tion or expression of transgenic proteins, are only now beginning to
be explored [
211
-
215
]. Research and development on other domains
of the amplicon biology or technology are just beginning, including
the possibility of engineering the tropism of amplicons or the devel-
opment of hybrid or combined vector systems that could eventually
achieve transport and delivery of the transgenic cassettes to regions of
the brain that are diffi cult to access without surgical intervention.
Amplicon research, however, is quite dynamic and the very large
transgenic capacity of these vectors offers unique possibilities for
the resolution of many problems that cannot be done with smaller
vector systems. Probably, the strongest future challenge that will
boost amplicon research and development will be the successful
application of these vectors to human beings. At the light of the
outstanding progress achieved in the last 10 years, we have few
doubts in that such an eventuality should arrive quite soon.
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