Chondroitinase ABC-Mediated Plasticity of Spinal Sensory Function

Cafferty, William B. J.; Bradbury, Elizabeth J.; Lidierth, Malcolm; Jones, Martyn G.; Duffy, Philip; Pezet, Sophie; McMahon, Stephen B.

doi:10.1523/jneurosci.3877-08.2008

Cited by 104 publications

(89 citation statements)

References 54 publications

(72 reference statements)

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“…We refrained from using such high MOI in our OEC cultures as even at our relatively low transduction rates sufficient ChABC was secreted. This was comparable to concentrations that have produced significant functional improvements in vivo in rat SCI models (11,16). Despite the robust levels of ChABC seen in vitro, it is possible that a proportion of OMCs will not survive following SCI transplantation (73).…”

Section: Discussionmentioning

confidence: 51%

“…However, injured axons are unable to regenerate across the site of injury in the central nervous system because of the presence of an array of inhibitory cues present within the scar (For a review, see 5,6), in particular chondroitin sulphate proteoglycans (CSPGs) (7)(8)(9)(10). Digestion of CSPGs with the bacterial enzyme chondroitinase ABC (ChABC), following local delivery to the spinal cord, has led to axon regeneration, plastic neuronal rearrangements and functional recovery following section or crush injury in laboratory animal SCI models (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Encouragingly, these findings have also been found using clinically relevant contusive injury rodent models (22,23) and large animal models such as cats and squirrel monkeys (19,24,25).…”

Section: Introductionmentioning

confidence: 99%

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Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

Carwardine

Wong

Fawcett

et al. 2016

Journal of the Neurological Sciences

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A multitude of factors must be overcome following spinal cord injury (SCI) in order to achieve clinical improvement in patients. It is thought that by combining promising therapies these diverse factors could be combatted with the aim of producing an overall improvement in function. Chondroitin sulphate proteoglycans (CSPGs) present in the glial scar that forms following SCI present a significant block to axon regeneration. Digestion of CSPGs by chondroitinase ABC (ChABC) leads to axon regeneration, neuronal plasticity and functional improvement in preclinical models of SCI. However, the enzyme activity decays at body temperature within 24-72 hours, limiting the translational potential of ChABC as a therapy. Olfactory ensheathing cells (OECs) have shown huge promise as a cell transplant therapy in SCI. Their beneficial effects have been demonstrated in multiple small animal SCI models as well as in naturally occurring SCI in canine patients. In the present study, we have genetically modified canine OECs from the mucosa to constitutively produce enzymatically active ChABC. We have developed a lentiviral vector that can deliver a mammalian modified version of the ChABC gene to mammalian cells, including OECs. Enzyme production was quantified using the Morgan-Elson assay that detects the breakdown products of CSPG digestion in cell supernatants. We confirmed our findings by immunolabelling cell supernatant samples using Western blotting. OECs normal cell function was unaffected by genetic modification as demonstrated by normal microscopic morphology and the presence of the low affinity neurotrophin receptor (p75 NGF ) following viral transduction. We have developed the means to allow production of active ChABC in combination with a promising cell transplant therapy for SCI repair.

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Section: Discussionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

Carwardine

Wong

Fawcett

et al. 2016

Journal of the Neurological Sciences

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“…Intradermal injections of CTB were used to reveal the spinal projections of small groups of myelinated cutaneous afferents innervating a patch of skin in the C6 dermatome. Cutaneous afferents labeled in this manner are localized exclusively within the C6 segment of the spinal cord in a restricted region of laminae III and IV in the dorsal horn (24). Myelinated sensory axons supplying the triceps muscle were labeled by injecting 1-2 μL of CTB directly into the triceps muscle nerve, as described above.…”

Section: Methodsmentioning

confidence: 99%

Topographically specific regeneration of sensory axons in the spinal cord

Harvey

Gong

Rossomando

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Artemin, a member of the glial-derived neurotrophic factor family, promotes robust regeneration of sensory axons after dorsal root crush. We report here that several classes of sensory axons regenerate to topographically appropriate regions of the dorsal horn with artemin treatment. Projections of regenerated muscle and cutaneous myelinated sensory afferents are restricted to the correct spinal segments and to appropriate regions within spinal gray matter. Regenerated unmyelinated axons expressing calcitonin gene-related peptide project only to superficial laminae of the dorsal horn, where uninjured nociceptive afferents project normally. In contrast, intraventricular infusion of a soluble form of the Nogo receptor that blocks the action of several myelin-associated inhibitory proteins promotes relatively unrestricted regeneration of sensory axons throughout the dorsal white and gray matter of the spinal cord. These results demonstrate that cues capable of guiding regenerating axons to appropriate spinal targets persist in the adult mammalian cord, but only some methods of stimulating regeneration allow the use of these cues by growing axons.artemin | central nervous system regeneration | dorsal root | soluble Nogo receptor peptide | specificity G rowth of damaged axons in the adult spinal cord is inhibited by the presence of myelin-associated proteins, up-regulation of proteoglycan expression, and the absence of appropriate growth factors. Several agents that can partially overcome this inhibition permit some regeneration of spinal axons in contusion or transaction models of spinal cord injury (SCI) (1-4); however, the limited regeneration and difficulty in labeling specific subclasses of axons with known projection patterns within the spinal cord have impeded progress in determining whether these regenerated projections are specific.The regeneration of sensory axons into the spinal cord after dorsal root (DR) crush provides a useful preparation for assessing the precision with which regenerating axons project back to appropriate target areas within the central nervous system (CNS). Regrowth of damaged sensory axons within the spinal cord can be visualized by injecting neurotracers into peripheral nerves. Identification of individual classes of axons can be achieved by making injections close to target tissues where nerve branches contain single classes of sensory afferents. Because only the DRs are damaged, the architecture of the spinal cord is left intact, allowing clear identification of the central projections of regenerated axons.Without treatment, sensory axons regenerate only to the DR entry zone (DREZ), where they encounter inhibitory barriers within the CNS (5, 6). Application of two agents-a soluble Nogo receptor peptide (sNgR), which binds to Nogo receptor ligands and abrogates their inhibitory effect (7), and artemin (ART), a member of the glial-derived neurotrophic factor familypromote robust regeneration of sensory axons after DR crush (8, 9). The specificity of projections of specific classes of...

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“…Chondroitin sulfate (CS) polysaccharides and their associated proteoglycans (CSPGs) are the principal inhibitory components of the glial scar, which forms after neuronal damage and acts as a barrier to axon regeneration (1)(2)(3). It is well established that the inhibitory activity of CSPGs is derived from their CS chains, as chondroitinase ABC (ChABC) treatment promotes axon regeneration, sprouting, and functional recovery after injury in vivo (4)(5)(6). However, the mechanisms by which CS polysaccharides inhibit axon growth are poorly understood.…”

mentioning

confidence: 99%

A sulfated carbohydrate epitope inhibits axon regeneration after injury

Brown

Xia

Zhuang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

140

178

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Chondroitin sulfate proteoglycans (CSPGs) represent a major barrier to regenerating axons in the central nervous system (CNS), but the structural diversity of their polysaccharides has hampered efforts to dissect the structure-activity relationships underlying their physiological activity. By taking advantage of our ability to chemically synthesize specific oligosaccharides, we demonstrate that a sugar epitope on CSPGs, chondroitin sulfate-E (CS-E), potently inhibits axon growth. Removal of the CS-E motif significantly attenuates the inhibitory activity of CSPGs on axon growth. Furthermore, CS-E functions as a protein recognition element to engage receptors including the transmembrane protein tyrosine phosphatase PTPσ, thereby triggering downstream pathways that inhibit axon growth. Finally, masking the CS-E motif using a CS-Especific antibody reversed the inhibitory activity of CSPGs and stimulated axon regeneration in vivo. These results demonstrate that a specific sugar epitope within chondroitin sulfate polysaccharides can direct important physiological processes and provide new therapeutic strategies to regenerate axons after CNS injury.

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Chondroitinase ABC-Mediated Plasticity of Spinal Sensory Function

Cited by 104 publications

References 54 publications

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

Topographically specific regeneration of sensory axons in the spinal cord

A sulfated carbohydrate epitope inhibits axon regeneration after injury

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