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7.2.2 Controlled Release of chABC
In spite of promising results, diffusion of chABC into deep regions of the spinal
cord and brain is limited when delivered intrathecally due to overfl ow beyond the
intrathecal space and loss of bioactivity [ 42 ]. As such, controlled release systems
(also see Sect. 7.6.1), such as hydrogel scaffolds and microspheres, have been
explored as a method for direct, prolonged chABC administration. For example,
Hyatt et al. demonstrated that controlled release from a fi brin delivery system
afforded increased concentrations of bioactive chABC and enhanced CSPG degra-
dation surrounding the lesion site compared to intraspinal injections [ 43 ]. Other
groups have corroborated the use of natural hydrogel systems for sustained and
controlled release of chABC to the injury site in murine models of SCI, recording
stable release and augmented preservation of bioactivity [ 42 , 44 , 45 ]. Further,
Huang et al. found that chABC loaded into poly-lactic acid microspheres is an
effective method for preserving bioactivity and delivering chABC [ 45 ].
7.2.3 Genetic Engineering Approaches to Limit CSPG levels
Recently, researchers have explored genetic engineering approaches to imitate the
effects chABC administration. Zhao et al. employed lentiviral vectors in a rat model
of corticospinal tract lesion and observed signifi cant degradation of CSPGs in the
injured brain following intracortical injections of lentiviral vectors containing the
chABC gene [ 46 ]. This reduction in CSPGs was correlated with marked reduction in
axonal degeneration and augmented sprouting and short-range regeneration of corti-
cospinal axons. The results of this study were corroborated by Bartus et al. [ 47 ]. An
in vitro model of SCI using a Tet-On adenoviral vector encoding chABC also exhib-
ited signifi cant CSPG degradation in treatment groups [ 48 ]. In addition to increasing
the expression of chABC, Donnelly et al. explored the effects of knocking down
expression of one of the major pathways of CSPG formation, NG-2 [ 49 ]. They found
that rats treated with short hairpin (sh) RNA designed to target NG-2 delivered by
lentiviral vectors exhibited signifi cantly reduced glial scar volume[ 49 ].
7.2.4 Drug Delivery Approaches to Enhance Neural Sprouting
Aside from high inhibitory levels of CSPG within the injury penumbra, additional
inhibitory signals are readily present, including the neurite growth inhibitor Nogo-A,
a myelin-associated protein. As such, researchers are investigating approaches to
neutralize the inhibitory effects of Nogo-A. Infusion of Nogo-A antibodies 24 h
after experimental stroke signifi cantly increased axonal sprouting, subsequently
promoting recovery from middle cerebral artery occlusion [ 50 ]. Moreover, delayed
A. Roussas et al.