Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury

Burnside, Emily R.; Winter, Fred de; Didangelos, Athanasios; James, Nicholas D.; Andreica, Elena-Cristina; Horsfall, Hugo Layard; Muir, Elizabeth M.; Verhaagen, Joost; Bradbury, Elizabeth J.

doi:10.1093/brain/awy158

Cited by 96 publications

(98 citation statements)

References 75 publications

(117 reference statements)

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“…It can significantly propel functional recovery in many kinds of SCI models and can also be combined with other treatments (e.g., stem cell transplantation, peripheral nerve autografts, and conditioning treatment) to achieve better results (Alilain et al, 2011;DePaul et al, 2015;Suzuki et al, 2017;Warren et al, 2018). Other studies on chondroitinase ABC aim to innovate the delivery route to promote clinical applications (Burnside et al, 2018;Hu et al, 2018). The receptors of CSPGs are also potential targets for therapeutic strategies.…”

Section: Strategies Targeting Cspgsmentioning

confidence: 99%

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

Yang

Dai

Chen

et al. 2020

Front. Cell. Neurosci.

146

161

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Recovery from spinal cord injury (SCI) remains an unsolved problem. As a major component of the SCI lesion, the glial scar is primarily composed of scar-forming astrocytes and plays a crucial role in spinal cord regeneration. In recent years, it has become increasingly accepted that the glial scar plays a dual role in SCI recovery. However, the underlying mechanisms of this dual role are complex and need further clarification. This dual role also makes it difficult to manipulate the glial scar for therapeutic purposes. Here, we briefly discuss glial scar formation and some representative components associated with scar-forming astrocytes. Then, we analyze the dual role of the glial scar in a dynamic perspective with special attention to scar-forming astrocytes to explore the underlying mechanisms of this dual role. Finally, taking the dual role of the glial scar into account, we provide several pieces of advice on novel therapeutic strategies targeting the glial scar and scar-forming astrocytes.

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Section: Strategies Targeting Cspgsmentioning

confidence: 99%

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

Yang

Dai

Chen

et al. 2020

Front. Cell. Neurosci.

146

161

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“…Lentiviral vector (LV) gene delivery of mChABC achieved long-term expression in the contused rat spinal cord which resulted in large-scale CSPG degradation and improved behavioural scores (Bartus et al, 2014). This team further developed an immune-evasive Tet-on inducible LV-mChABC vector that allows for regulated gene therapy in efforts to move towards clinical translation (Burnside et al, 2018). While LV-mChABC gene therapy has undeniable benefit, there remains concern about the safety of the use of the therapy in humans.…”

Section: Introductionmentioning

confidence: 99%

Astrocyte-selective AAV-ADAMTS4 gene therapy combined with hindlimb rehabilitation promotes functional recovery after spinal cord injury

Griffin

Fackelmeier

Clemett

et al. 2019

Preprint

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Chondroitin sulphate proteoglycans (CSPGs) are inhibitors to axon regeneration and plasticity. Bacterial chondroitinase ABC degrades CSPGs and has been extensively reported to be therapeutic after SCI but there remain concerns for its clinical translation. A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS4) is a human enzyme that catalyses the proteolysis of CSPG protein cores. Infusion of ADAMTS4 into the damaged spinal cord was previously shown to improve functional recovery after SCI, however, this therapy is limited in its enzyme form. Adeno-associated viral (AAV) vector gene therapy has emerged as the vector of choice for safe, robust and long-term transgene expression in the central nervous system. Here, an AAV expression cassette containing ADAMTS4 under the control of the astrocytic GfaABC 1 D promoter was packaged into an AAV5 vector. Sustained expression of ADAMTS4 was achieved in vitro and in vivo, leading to widespread degradation of CSPGs. AAV-ADAMTS4 resulted in significantly decreased lesion size, increased sprouting of hindlimb corticospinal tract axons, increased serotonergic fiber density caudal to the injury, and improved functional recovery after moderate contusive SCI.Hindlimb-specific exercise rehabilitation was used to drive neuroplasticity towards improving functional connections. The combination of hindlimb rehabilitation with AAV-ADAMTS4 led to enhanced functional recovery after SCI. Thus, widespread and long-term degradation of CSPGs through AAV-ADAMTS4 gene therapy in a combinational approach with rehabilitation represents a promising candidate for further preclinical development. AbbreviationsAAV Adeno-associated virus ADAMTS A disintegrin and metalloproteinase with thrombospondin motifs ChABC Chondroitinase ABC CS-GAG Chondroitin sulphate glycosaminoglycan CSPG Chondroitin sulphate proteoglycan ECM Extracellular matrix GAG Glycosaminoglycan LV Lentiviral vector

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“…improve motor outcomes, these findings present promise for ChABC treatment as a potential new avenue for providing neuroprotection in PD. In this respect, it is reassuring that alternative formulations with enhanced stability [46] and alternative longer-term means of ChABC delivery, such as doxycycline-inducible gene delivery [47], are being investigated to achieve a more clinically translatable treatment.…”

Section: Resultsmentioning

confidence: 99%

Chondroitinase ABC reduces dopaminergic nigral cell death and striatal terminal loss in a 6-hydroxydopamine partial lesion mouse model of Parkinson’s disease

Fletc

Moon

Duty

2019

Preprint

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BackgroundParkinson's disease (PD) is characterised by dopaminergic cell loss within the substantia nigra pars compacta (SNc) that leads to reduced striatal dopamine content and resulting motor deficits. Identifying new strategies to protect these cells from degeneration and retain striatal dopaminergic innervation is therefore of great importance. Chondroitin sulphate proteoglycans (CSPGs) are recognised contributors to the inhibitory extracellular milieu known to hinder tissue recovery following CNS damage. Digestion of these molecules by the bacterial lyase chondroitinase ABC (ChABC) has been shown to promote functional recovery in animal models of neurological injury. Although ChABC has been shown to promote sprouting of dopaminergic axons following transection of the nigrostriatal pathway, its ability to protect against nigrostriatal degeneration in a toxin-based module with better construct validity for PD has yet to be explored. Here we examined the neuroprotective efficacy of ChABC treatment in the full and partial 6-hydroxydopamine (6-OHDA) lesion mouse models of PD. ResultsIn mice bearing a full 6-OHDA lesion, ChABC treatment failed to protect against the loss of either nigral cells or striatal terminals. In contrast, in mice bearing a partial 6-OHDA lesion, ChABC treatment significantly protected cells of the rostral SNc, which remained at more than double the numbers seen in vehicle-treated animals. In the partial lesion model, ChABC treatment also significantly preserved dopaminergic fibres of the rostral dorsal striatum which increased from 15.3 ± 3.5% of the intact hemisphere in saline-treated animals to 36.3 ± 6.5% in the ChABC-treated group. These protective effects of ChABC treatment were not accompanied by improvements in either the cylinder or amphetamine-induced rotations tests of motor function. ConclusionsChABC treatment provided significant protection against a partial 6-OHDA lesion of the nigrostriatal tract although the degree of protection was not sufficient to improve motor outcomes. These results support further investigations into the benefits of ChABC treatment for providing neuroprotection in PD.

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Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury

Cited by 96 publications

References 75 publications

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

Astrocyte-selective AAV-ADAMTS4 gene therapy combined with hindlimb rehabilitation promotes functional recovery after spinal cord injury

Chondroitinase ABC reduces dopaminergic nigral cell death and striatal terminal loss in a 6-hydroxydopamine partial lesion mouse model of Parkinson’s disease

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