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

Griffin, Jarred M.; Fackelmeier, Barbara; Clemett, Connor A.; Fong, Dahna M.; Mouravlev, Alexandre; Young, Deborah; O’Carroll, Simon J.

doi:10.1016/j.expneurol.2020.113232

Cited by 30 publications

(19 citation statements)

References 56 publications

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“…This time-point was chosen as natural recovery reaches a plateau in rats with thoracic injury at the position of the implant by 5-weeks. [24] Both animals showed no impairment with consistent scores of 21/21 across this extended period (Figure 2d), in contrast to a previous report of moderate hind-limb deficits at 6 weeks after insertion of a polyimide implant. [9] Due to the consistent scoring in these two 5-week animals we elected to move onto longer-term implantations, which included an external connector (see Section 2).…”

Section: Insertion Of the Bioelectronic Implant Did Not Affect Hind-l...contrasting

confidence: 58%

“…We envisage that 12 weeks is sufficiently long for treatments to influence regeneration and any resulting functional improvements to be observed in a rat model of SCI. [24] In vivo electrophysiological recordings can be contaminated by noise and artifactual signals that affect subsequent analysis and interpretation of the signal. Artifacts may be of extrinsic origin, such as a noisy electromagnetic environment or the measurement instrument itself, or they may be of intrinsic or physiological origin, such as non-neural bioelectrical signals.…”

Section: Discussionmentioning

confidence: 99%

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A Subdural Bioelectronic Implant to Record Electrical Activity from the Spinal Cord in Freely Moving Rats

et al. 2022

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Bioelectronic devices have found use at the interface with neural tissue to investigate and treat nervous system disorders. Here, the development and characterization of a very thin flexible bioelectronic implant inserted along the thoracic spinal cord in rats directly in contact with and conformable to the dorsal surface of the spinal cord are presented. There is no negative impact on hind-limb functionality nor any change in the volume or shape of the spinal cord. The bioelectronic implant is maintained in rats for a period of 12 weeks. The first subdural recordings of spinal cord activity in freely moving animals are presented; rats are plugged in via a recording cable and allowed to freely behave and move around on a raised platform. Recordings contained multiple distinct voltage waveforms spatially localize to individual electrodes. This device has great potential to monitor electrical signaling in the spinal cord after an injury and in the future, this implant will facilitate the identification of biomarkers in spinal cord injury and recovery, while enabling the delivery of localized electroceutical and chemical treatments.

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Section: Insertion Of the Bioelectronic Implant Did Not Affect Hind-l...contrasting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

A Subdural Bioelectronic Implant to Record Electrical Activity from the Spinal Cord in Freely Moving Rats

et al. 2022

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“…To confirm that overexpression of USP18 promotes functional recovery and limits inflammation after SCI in mice, we injected astrocytespecific adeno-associated virus serotype 9 (AAV9) expressing USP18 (AAV-USP18) into the injured spinal cord immediately after SCI, as previously reported (Griffin et al, 2020;Klaw, Xu, & Tom, 2013). Immunoblotting revealed that injection of AAV-USP18 increased expression of USP18 by 1.9-and 1.7-fold in sham-operated and SCI mice, respectively (Figure S4a).…”

Section: Overexpression Of Usp18 In Astrocytes Promotes Functional Recovery and Limits Infiltration Of Inflammatory Cells After Scisupporting

confidence: 57%

Deubiquitinase USP18 regulates reactive astrogliosis by stabilizing SOX9

Liu

Zhou

et al. 2021

Glia

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Reactive astrogliosis is a pathological feature of spinal cord injury (SCI). The ubiquitin‐proteasome system plays a crucial role in maintaining protein homeostasis and has been widely studied in neuroscience. Little, however, is known about the underlying function of deubiquitinating enzymes in reactive astrogliosis following SCI. Here, we found that ubiquitin‐specific protease 18 (USP18) was significantly upregulated in astrocytes following scratch injury, and in the injured spinal cord in mice. Knockdown of USP18 in vitro and conditional knockout of USP18 in astrocytes (USP18 CKO) in vivo significantly attenuated reactive astrogliosis. In mice, this led to widespread inflammation and poor functional recovery following SCI. In contrast, overexpression of USP18 in mice injected with adeno‐associated virus (AAV)‐USP18 had beneficial effects following SCI. We showed that USP18 binds, deubiquitinates, and thus, stabilizes SRY‐box transcription factor 9 (SOX9), thereby regulating reactive astrogliosis. We also showed that the Hedgehog (Hh) signaling pathway induces expression of USP18 through Gli2‐mediated transcriptional activation after SCI. Administration of the Hh pathway activator SAG significantly increased reactive astrogliosis, reduced lesion area and promoted functional recovery in mice following SCI. Our results demonstrate that USP18 positively regulates reactive astrogliosis by stabilizing SOX9 and identify USP18 as a promising target for the treatment of SCI.

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“…A number of studies have used AAV vectors containing the 681 bp gfaABC 1 D with the goal of obtaining astrocyte specificity (Xie et al, 2010;Theofilas et al, 2011;Dirren et al, 2014;Dvorzhak et al, 2016;Vagner et al, 2016;Taschenberger et al, 2017;Griffin et al, 2019Griffin et al, , 2020Testen et al, 2020). While several studies show good evidence of astrocyte specificity (Xie et al, 2010;Theofilas et al, 2011), other studies report transduction of other cell types (Taschenberger et al, 2017;Griffin et al, 2019).…”

Section: Aav-based Approaches For Targeting Transgene Expression To Astrocytesmentioning

confidence: 99%

AAV Targeting of Glial Cell Types in the Central and Peripheral Nervous System and Relevance to Human Gene Therapy

O’Carroll

Cook

Young

2021

Front. Mol. Neurosci.

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Different glial cell types are found throughout the central (CNS) and peripheral nervous system (PNS), where they have important functions. These cell types are also involved in nervous system pathology, playing roles in neurodegenerative disease and following trauma in the brain and spinal cord (astrocytes, microglia, oligodendrocytes), nerve degeneration and development of pain in peripheral nerves (Schwann cells, satellite cells), retinal diseases (Müller glia) and gut dysbiosis (enteric glia). These cell type have all been proposed as potential targets for treating these conditions. One approach to target these cell types is the use of gene therapy to modify gene expression. Adeno-associated virus (AAV) vectors have been shown to be safe and effective in targeting cells in the nervous system and have been used in a number of clinical trials. To date, a number of studies have tested the use of different AAV serotypes and cell-specific promoters to increase glial cell tropism and expression. However, true glial-cell specific targeting for a particular glial cell type remains elusive. This review provides an overview of research into developing glial specific gene therapy and discusses some of the issues that still need to be addressed to make glial cell gene therapy a clinical reality.

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

Cited by 30 publications

References 56 publications

A Subdural Bioelectronic Implant to Record Electrical Activity from the Spinal Cord in Freely Moving Rats

A Subdural Bioelectronic Implant to Record Electrical Activity from the Spinal Cord in Freely Moving Rats

Deubiquitinase USP18 regulates reactive astrogliosis by stabilizing SOX9

AAV Targeting of Glial Cell Types in the Central and Peripheral Nervous System and Relevance to Human Gene Therapy

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