Gene Therapy Approaches to Promoting Axonal Regeneration After Spinal Cord Injury - Gene Delivery and Therapy for Neurological Disorders - page 156

and increase the expression of ATF-3 [ 28 ] in injured neurons. Viral
vector mediated expression of ATF-3 in dorsal root ganglion (DRG)
neurons is reported to enhance neurite outgrowth [ 29 ]. Expression
of both STAT3 and the constitutively active STAT3c in DRG neu-
rons using AAV increased terminal and collateral spouting of the
lesioned central branches of DRG neurons [ 30 ]. Activation of
Smad1 in mouse DRG neurons by intrathecal delivery of AAV-bone
morphogenetic protein is also able to promote signifi cant growth of
the ascending sensory axons across the lesion center of a T8 spinal
cord dorsal hemisection [ 31 ]. Another transcription factor CREB is
also involved in the activation of the regeneration mechanism of
DRG neurons and expression of a constitutively active CREB in
DRG neurons is able to promote regeneration of the lesioned
ascending sensory axons in the dorsal column [ 32 ]. Cortical motor
neurons are considered to have very weak regeneration capacity.
However, in a recent study, transduction of corticospinal tract
(CST) neurons with STAT3 is shown to promote corticospinal
remodelling and functional recovery after spinal cord injury [ 33 ].
Retinoic acid receptors are nuclear receptors that act as tran-
scription factors by binding to retinoic acid response elements and
promoting the transcription of downstream genes. Retinoic acid
signaling plays important roles in the development, regeneration,
and maintenance of the nervous system [ 34 ]. Expression of reti-
noic acid receptor 2) in rat DRG neurons using an

equine infectious anemia viral vector enabled the crushed dorsal
root axons to regenerate across the dorsal root entry zone and
project into the grey matter of the spinal cord [ 35 ]. The same lab
also reported that expression of RAR

ʲ 2 (RAR ʲ

2 in rat cortical neurons pro-
moted the regeneration of CST axons [ 36 ].
In recent years, it is believed the proregenerative transcrip-
tional machinery is silenced or repressed in adult CNS neurons,
which accounts for their irresponsiveness to injury. However, the
regenerative machinery can be reactivated by modulating the
expression of growth-related genes. Gaub et al. over-expressed his-
tone acetyltransferases p300 in injured retinal ganglion cells and
enhanced the regeneration of optic nerve [ 37 ]. It was found that
p300 acetylates histone H3 and the proregenerative transcription
factors p53 and CCAAT-enhancer binding proteins, and also
directly occupies and acetylates the promoters of the growth-
associated protein-43 (GAP-43), coronin 1B, and SPRR1A and
drives the gene expression of several regeneration-associated genes.
These studies demonstrate the potential in enhancing axonal
regeneration by activating growth promoting transcription factors.
However, as many transcription factors are shown to induce axonal
regeneration, it needs to fi nd out how these transcription factors
coordinate their actions and whether these transcription factors
have synergistic effects when co-expressed or co-activated.

ʲ