Peripherally delivered Adeno-associated viral vectors for spinal cord injury repair

Sydney-Smith, Jared D.; Spejo, Aline Barroso; Warren, Philippa M.; Moon, Lawrence

doi:10.1016/j.expneurol.2021.113945

Cited by 5 publications

(3 citation statements)

References 109 publications

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“…We used an AAV1-CMV mediated gene therapy to deliver a therapeutic transgene via injection into peripheral muscle. This is an effective and safe delivery system used previously in human patients in the Glybera therapy and also in numerous preclinical studies ( Sydney-Smith et al, 2021b ; Kakanos and Moon, 2019 ; Wang et al, 2018 ; Zhou et al, 2003 ; Chen et al, 2006 ; Fortun et al, 2009 ; Petruska et al, 2010 ). NT3 is safe and well-tolerated in human adults when given peripherally at high doses ( Sahenk et al, 2005 ; Parkman et al, 2003 ; Coulie et al, 2000 ) and an AAV-tMCK-NT3 treatment applied through injection into the leg muscle has recently been approved for use in a phase 1 clinical trial ( NCT03520751 ).…”

Section: Discussionmentioning

confidence: 99%

Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb function and stability after thoracic contusion

Sydney-Smith

Koltchev

Moon

et al. 2023

Experimental Neurology

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Section: Discussionmentioning

confidence: 99%

Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb function and stability after thoracic contusion

Sydney-Smith

Koltchev

Moon

et al. 2023

Experimental Neurology

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“…We used an AAV1-mediated gene therapy to deliver NT3 via injection into peripheral muscle. This has the benefit of being an effective and safe delivery system (Fortun et al, 2009, Petruska et al, 2010) (e.g., as used in Glybera for another transgene) (Sydney-Smith et al, 2021b, Kakanos and Moon, 2019, Wang et al, 2018, Zhou et al, 2003, Chen et al, 2006). Neurotrophin-3 is safe and well-tolerated in human adults when given peripherally at high doses (Sahenk et al, 2005, Parkman et al, 2003, Coulie et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb function and stability after thoracic contusion in rats

Sydney-Smith

Koltchev

Moon

et al. 2022

Preprint

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It has been reported that intramuscular injection of an Adeno-associated viral vector serotype 1 (AAV1) encoding Neurotrophin-3 (NT3) into hindlimb muscles 24 hours after a severe T9 contusion in rats induced lumbar spinal neuroplasticity, partially restored locomotive function and reduced spasms during swimming. Here we investigated whether a targeted delivery of NT3 to lumbar and thoracic motor neurons 48 hours following a severe contusive injury aids locomotive recovery in rats. AAV1-NT3 was injected into the tibialis anterior, gastrocnemius and rectus abdominus muscles 48-hours following trauma, persistently elevating serum levels of the neurotrophin. NT3 improved trunk stability, accuracy of stepping during skilled locomotive tasks, and alternation of the hindlimbs during swimming, but it had no effect on gross locomotion function in the open field. The number of vGlut1+ (likely proprioceptive afferent) boutons on gastrocnemius α-motor neurons was increased after injury but normalised following NT3 treatment suggestive of a mechanism in which the functional effects may be mediated through proprioceptive feedback. Ex vivo MRI revealed substantial loss of grey and white matter at the lesion epicentre but no effect of delayed NT3 treatment to induce neuroprotection or prevent secondary damage. Spasms and hyperreflexia were not reliably induced in this severe injury model suggesting a more complex anatomical or physiological cause to their induction. We have shown that delayed intramuscular AAV-NT3 treatment can promote recovery in skilled stepping and coordinated swimming supporting a role for NT3 as a therapeutic strategy for spinal injuries potentially through modulation of somatosensory feedback.

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“…rAAV is more widely used than other viral vectors because it can achieve a high level of transduction within a few weeks that can be maintained throughout the life cycle of the organism ( Flotte, 2004 ). The peripheral nervous system, including the autonomic nervous system (ANS) ( Sydney-Smith et al., 2021 ) and enteric nervous system (ENS), can be transduced following systemic rAAV injection ( Chan et al., 2017 ). Furthermore, the low immunogenicity of rAAV further promotes its application in the biomedical field ( Buckinx and Timmermans, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Adeno-associated virus vector intraperitoneal injection induces colonic mucosa and submucosa transduction and alters the diversity and composition of the faecal microbiota in rats

Lian

Bai

et al. 2022

Front. Cell. Infect. Microbiol.

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BackgroundViral vector technology, especially recombinant adeno-associated virus vector (rAAV) technology, has shown great promise in preclinical research for clinical applications. Several studies have confirmed that rAAV can successfully transduce the enteric nervous system (ENS), and rAAV gene therapy has been approved by the Food and Drug Administration (FDA) for the treatment of the early childhood blindness disease Leber congenital amaurosis and spinal muscular atrophy (SMA). However, until now, it has not been possible to determine the effect of AAV9 on intestinal microbiota. MethodsWe examined the efficiency of AAV9-mediated ascending colon, transverse colon and descending colon transduction through intraperitoneal (IP) injection, performed 16S rRNA gene amplicon sequencing and analysed specific faecal microbial signatures following AAV9 IP injection via bioinformatics methods in Sprague–Dawley (SD) rats. ResultsOur results showed (1) efficient transduction of the mucosa and submucosa of the ascending, transverse, and descending colon following AAV9 IP injection; (2) a decreased alpha diversity and an altered overall microbial composition following AAV9 IP injection; (3) significant enrichments in a total of 5 phyla, 10 classes, 13 orders, 15 families, 29 genera, and 230 OTUs following AAV9 IP injection; and (4) AAV9 can significantly upregulate the relative abundance of anaerobic microbiota which is one of the seven high-level phenotypes that BugBase could predict.ConclusionIn summary, these data show that IP injection of AAV9 can successfully induce the transduction of the colonic mucosa and submucosa and alter the diversity and composition of the faecal microbiota in rats.

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Peripherally delivered Adeno-associated viral vectors for spinal cord injury repair

Cited by 5 publications

References 109 publications

Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb function and stability after thoracic contusion

Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb function and stability after thoracic contusion

Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb function and stability after thoracic contusion in rats

Adeno-associated virus vector intraperitoneal injection induces colonic mucosa and submucosa transduction and alters the diversity and composition of the faecal microbiota in rats

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