Transplantation and repair: Combined cell implantation and chondroitinase delivery prevents deterioration of bladder function in rats with complete spinal cord injury

Fouad, Karim; Pearse, Damien D.; Tetzlaff, Wolfram; Vavrek, Romana

doi:10.1038/sc.2009.10

Cited by 52 publications

(35 citation statements)

References 21 publications

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“…The combination of OECs and ChABC (plus a Schwann cell graft) has already been tested in a complete spinal cord transection model where the addition of ChABC improved both bladder and motor function (45,46). The feasibility of genetically modifying OECs from the olfactory bulb for SCI was previously demonstrated by Ruitenberg et al (57).…”

Section: Discussionmentioning

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: 99%

“…Their beneficial effect on locomotion has been demonstrated in rodent models of SCI (39)(40)(41)(42)(43) and in companion dogs (44). Further, combining spinal cord injection of OECs and ChABC has a greater effect on locomotion and bladder voiding than either therapy alone (45,46).…”

Section: Abbreviationsmentioning

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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show abstract

“…Bladder function was also studied in a thoracic transection model, using a similar treatment with Schwann cells, oECs and ChABC [24] . in the combined-treatment group, increased bladder size and decreased amount of disorganized smooth muscle fibers and collagen deposit were found in comparison to the control group.…”

Section: Schwann Cells Oecs and Chabcmentioning

confidence: 99%

Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier

Zhao

Fawcett

2013

Neurosci. Bull.

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After spinal cord injury (SCi), re-establishing functional circuitry in the damaged central nervous system (CNS) faces multiple challenges including lost tissue volume, insufficient intrinsic growth capacity of adult neurons, and the inhibitory environment in the damaged CNS. Several treatment strategies have been developed over the past three decades, but successful restoration of sensory and motor functions will probably require a combination of approaches to address different aspects of the problem. Degradation of the chondroitin sulfate proteoglycans with the chondroitinase ABC (ChABC) enzyme removes a regeneration barrier from the glial scar and increases plasticity in the CNS by removing perineuronal nets. its mechanism of action does not clash or overlap with most of the other treatment strategies, making ChABC an attractive candidate as a combinational partner with other methods. in this article, we review studies in rat SCi models using ChABC combined with other treatments including cell implantation, growth factors, myelin-inhibitory molecule blockers, and ion channel expression. We discuss possible ways to optimize treatment protocols for future combinational studies. To date, combinational therapies with ChABC have shown synergistic effects with several other strategies in enhancing functional recovery after SCi. These combinatorial approaches can now be developed for clinical application.

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“…Bladder emptying involves a complex synergy between the pontine micturition center, the sympathetic and parasympathetic nervous system and motoneurons in the spinal cord 1 . Spinal cord injury (SCI) severely impacts bladder function, and leads to neurogenic bladder dysfunction.…”

Section: Introductionmentioning

confidence: 99%

“…Increased detrusor pressure and urinary retention result in alterations in bladder size and tissue composition 1,3 . Further deterioration of bladder function and frequent infections predispose renal damage and renal failure.…”

Section: Introductionmentioning

confidence: 99%

Multisystem Neuroprosthetic Training Improves Bladder Function After Severe Spinal Cord Injury

et al. 2013

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BACKGROUND: Severe spinal cord injury (SCI) leads to neurogenic bladder dysfunction. We recently developeda multi-system neuroprosthetic training program (MSNT) that promotes plastic changes capable of restoring refinedlocomotion in rats with severe SCI. We investigated whether MSNTinfluences the formation of posttraumatic bladder dysfunction. MATERIALS AND METHODS: Adult rats were randomly assigned to a SCI (n=8) and to a control intact (n=4) group. SCI consisted of two opposite lateral hemisections (T7, T11), thusinterrupting all direct supraspinal input. After SCI, 4 rats were subjected to MSNT, 4 rats were non-trained. After 8 weekswe performed urodynamics and evaluated kidney function (creatinine, cystatin C). Bladder investigation included morphological, histological and immunohistochemical evaluations. RESULTS: Bladder capacity increased 3-fold in trained and 7-fold in non-trained compared to intact animals. During filling,we found 2.7 ± 1.1 non-voiding contractions (NVC) in trained, compared to 12.6 ± 5.2 in non-trained rats. Bladder morphology was similar in trained and intact rats, non-trained ratsexhibited detrusor hypertrophycharacterized by increased detrusor thickness and decreased connective tissue to smooth muscle ratio. The general nerve density, labeled with PGP9.5, was significantly increased in trained and significantly decreased in non-trained rats. The relative proportion of NF200-postive afferent nerves was significantly lower in trained compared to intact and non-trained rats. NPY-positive fibers showed a significantly lower density in non-trained rats. CONCLUSIONS: MSNT effectively counteracts the formation of neurogenic bladder dysfunction after severe SCI and might contribute to preserving bladder function and preventing long-term complications in patients with severe SCI. MULTI-SYSTEM NEUROPROSTHETIC TRAINING IMPROVES BLADDER FUNCTION AFTER SEVERE SPINAL CORD INJURY

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Transplantation and repair: Combined cell implantation and chondroitinase delivery prevents deterioration of bladder function in rats with complete spinal cord injury

Cited by 52 publications

References 21 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

Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier

Multisystem Neuroprosthetic Training Improves Bladder Function After Severe Spinal Cord Injury

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