Gene Therapy Approaches to Promoting Axonal Regeneration After Spinal Cord Injury - Gene Delivery and Therapy for Neurological Disorders - page 154

growth inhibitory molecules [ 3 ], including intrathecal or intraspi-
nal administration of therapeutic agents like neurotrophic factors
[ 4 ], neutralizing antibodies for inhibitory molecules such as
Nogo-A [ 5 ], a Nogo receptor antagonistic peptide [ 6 ], a truncated
soluble Nogo receptor (sNgR) that acts as a decoy to block myelin
inhibitors [ 7 ], or chondroitinase ABC (ChABC) to degrade the
growth inhibitory chondroitin sulfate proteoglycans (CSPGs) in
the extracellular matrix and glial scar [ 8 ]. Most of those treatments
in animal models have shown a certain degree of success in pro-
moting axonal growth. However, conventional delivery of thera-
peutic agents has many limitations such as rapid degradation of the
agents, ineffi ciency in tissue penetration, and adverse effects on
nontarget cells. Such limitations can be overcome by gene therapy
approaches. Viral vectors carrying therapeutic genes under the con-
trol of cell type-specifi c promoters can be injected at the intended
site in the CNS to achieve local and cell-specifi c gene expression
[ 9 ]. Endogenous genes can also be knocked down similarly using
viral vectors carrying short-hairpin RNAs [ 10 ]. In addition, viral
vector mediated gene expression can last for months or years.
Long-term expression of therapeutic genes may be required as neu-
ral repair is a rather lengthy process. Long-distance axonal regen-
eration may also require sequential and appropriately distributed
expression of genetic factors, which may be achieved using induc-
ible gene expression systems [ 11 ]. Using viral vector based gene
delivery techniques, a variety of molecules have been delivered
to injured spinal cord or brain either in vivo or ex vivo [ 12 , 13 ].
In this chapter, we are only able to cite a limited number of studies
on certain types of targeted molecules.

As axotomy disrupts the retrograde transportation of target cell
derived trophic factors to reach neuronal soma, provision of vari-
ous neurotrophic factors such as nerve growth factor (NGF), neu-
rotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF),
glial cell line derived neurotrophic factor (GDNF), and ciliary neu-
rotrophic factor (CNTF) has been considered as a key component
in the strategies for neural repair [ 14 ]. Neurotrophic factors may
play multiple roles in the neural repair processes such as protecting
neuronal death after injury and enhancing axonal growth (regen-
eration and/or sprouting). They may also be able to overcome
inhibitory molecules in the CNS. Different populations of neurons
respond differently to different trophic factors and many neurons
express receptors for multiple trophic factors; therefore, delivery of
a combination of several trophic factors may achieve a much more
profound effect [ 15 ].
Growth factors can be delivered via ex vivo and in vivo routes.
In 1998 Zhang et al. reported that injection of adenoviral vector
carrying NT-3 cDNA into the ventral horn of the lumbar spinal
cord resulted in strong expression of the NT-3 in glial cells and

1.1 Delivery
of Neurotrophic
Factors