Lentiviral Vectors for Gene Delivery to the Nervous System - Gene Delivery and Therapy for Neurological Disorders - page 25

localized disease models. Viral vectors can effi ciently express either
single or multiple transgenes and transduction does not seem to
interfere with normal function [ 4 ]. Because viral vectors can incor-
porate a wide variety of regulatory elements, it is possible to achieve
short- or long-term transgene expression and to target specifi c
regions of the nervous system. Temporal and spatial control can
even be achieved by combining transgenic knock-in/knockout
strategies with viral vectors [ 9 ]. Indeed, recombinant viruses such
as adenoviruses, adeno-associated viruses, herpes viruses, poxvi-
ruses, retroviruses, and recently lentiviruses have been used in
applications both in clinical trials and laboratories [ 10 - 13 ].

1.3 Ideal Gene
Delivery Vehicle

Ideally, the production of a gene delivery vector should be simple.
The vector should be able to be produced in high titers, required
for human gene therapy, and preferable have the ability to be tar-
geted to specifi c molecules within the host's cells. Moreover, it
should have large cloning capacity, to carry small genes such as
insulin (350 bp) and large genes like dystrophin (12 kb cDNA).
Upon delivery, it should not elicit any signifi cant immune response
which would lead to its degradation from the host immune system.
The vector should specifi cally target a tissue or a cell type limiting
any nonspecifi c tissue targeting. Most importantly, the vector
should have the ability to transduce both dividing and non-divid-
ing cells such as neurons, hepatocytes and myocytes. The transgene
carried by the vector needs to be integrated specifi cally at a defi ned
locus of host's chromosomal DNA or maintained in the nucleus as
an extrachromosomal episome dividing and segregating with the
cell. Finally, a vector should be able to induce stable and long-term
transgene expression as certain diseases require sustained and life-
long expression of the therapeutic gene to achieve treatment.
Since these characteristics are diffi cult to fi nd in a single sys-
tem, the appropriate viral vector system should be carefully selected
for each specifi c application as they differ in terms of cloning capac-
ity, tropism, transgene expression duration, biosafety, immunoge-
nicity, and challenges in production method [ 14 ].

1.4 Lentiviral
Vectors in Gene
Therapy

Lentiviral vectors (LVs) are based on the single stranded RNA
(sRNA) lentiviruses, which are a subgroup of the retrovirus family.
Vectors based on lentiviruses are among the most promising
approaches for the treatment of neurological disorders as they are
able to integrate their genome into both mitotic, such as glia, and
post-mitotic cells, such as neurons [ 15 - 17 ]. Lentiviral vectors
combine advantages of large cloning capacity (8-10 kb) with stable
integration of transgene into the chromosome of target cells pro-
moting long-term expression and an attractive safe profi le due to
minimal infl ammatory response that does not compromise the
viability of their target. This is of high importance for gene therapy
applications for neurodegenerative diseases, since they often