Slow Infusion of Recombinant Adeno-Associated Viruses into the Mouse Cerebrospinal Fluid Space

Wang, Dan; Li, Jia; Tran, Karen; Burt, Daniel Robert; Zhong, Li; Gao, Guangping

doi:10.1089/hgtb.2017.250

Cited by 8 publications

(5 citation statements)

References 40 publications

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“…1), transduction was robust throughout the entire spinal cord. 38 Although we readily detected AAV-mediated ABCD1 expression after osmotic pump delivery by both Western blotting and immunofluorescence staining (Figs. 2 and 3), transgene-positive cells were much more diffuse for ABCD1 ( Fig.…”

Section: Discussionmentioning

confidence: 93%

Intrathecal Adeno-Associated Viral Vector-Mediated Gene Delivery for Adrenomyeloneuropathy

et al. 2019

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Mutations in the gene encoding the peroxisomal ATP-binding cassette transporter (ABCD1) cause elevations in very long-chain fatty acids (VLCFAs) and the neurodegenerative disease adrenoleukodystrophy (ALD). In most adults, this manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN). A challenge in virus-based gene therapy in AMN is how to achieve functional gene correction to the entire spinal cord while minimizing leakage into the systemic circulation, which could contribute to toxicity. In the present study, we used an osmotic pump to deliver adeno-associated viral (AAV) vector into the lumbar cerebrospinal fluid space in mice. We report that slow intrathecal delivery of recombinant AAV serotype 9 (rAAV9) achieves efficient gene transfer across the spinal cord and dorsal root ganglia as demonstrated with two different transgenes, GFP and ABCD1. In the Abcd1-/mouse, gene correction after continuous rAAV9-CBA-hABCD1 delivery led to a 20% decrease in VLCFA levels in spinal cord compared with controls. The major cell types transduced were astrocytes, vascular endothelial cells, and neurons. Importantly, rAAV9 delivered intrathecally by osmotic pump, in contrast to bolus injection, reduced systemic leakage into peripheral organs, particularly liver and heart tissue.

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Section: Discussionmentioning

confidence: 93%

Intrathecal Adeno-Associated Viral Vector-Mediated Gene Delivery for Adrenomyeloneuropathy

et al. 2019

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“…The right-side supranigral infusion was administered using an osmotic pump (model 2004, ALZET, Cupertino, CA, USA) connected to a cannula, as previously described (Wang et al, 2018a). Pumps were primed with 37°C sterile saline for 40 hours before implantation.…”

Section: Supranigral Infusionmentioning

confidence: 99%

Angiotensin-(1–7) reduces α-synuclein aggregation by enhancing autophagic activity in Parkinson’s disease

Gao

Chen

et al. 2022

Neural Regen Res

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“…The direction of spinal fluid flow in the cerebrospinal cavity is quite simple compared to the flow of blood in blood vessels, and it would easily reach the brain passively without involving the systemic circulation. Drugs and genes administered simply through the lumbar spinal cavity are distributed predominantly in the spinal cord rather than intracranially [62,63]. Previous studies have reported that the amount of intracranial drug solution administered through the spinal cavity of the lumbar spine is proportional to the volume of the solution and the time elapsed since administration [64].…”

Section: Discussionmentioning

confidence: 99%

Intracranial Gene Delivery Mediated by Albumin-Based Nanobubbles and Low-Frequency Ultrasound

Koga,

Kida,

Yamasaki

et al. 2024

Nanomaterials

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Research in the field of high-intensity focused ultrasound (HIFU) for intracranial gene therapy has greatly progressed over the years. However, limitations of conventional HIFU still remain. That is, genes are required to cross the blood-brain barrier (BBB) in order to reach the neurological disordered lesion. In this study, we introduce a novel direct intracranial gene delivery method, bypassing the BBB using human serum albumin-based nanobubbles (NBs) injected through a less invasive intrathecal route via lumbar puncture, followed by intracranial irradiation with low-frequency ultrasound (LoFreqUS). Focusing on both plasmid DNA (pDNA) and messenger RNA (mRNA), our approach utilizes LoFreqUS for deeper tissue acoustic penetration and enhancing gene transfer efficiency. This drug delivery method could be dubbed as the “Spinal Back-Door Approach”, an alternative to the “front door” BBB opening method. Experiments showed that NBs effectively responded to LoFreqUS, significantly improving gene transfer in vitro using U-87 MG cell lines. In vivo experiments in mice demonstrated significantly increased gene expression with pDNA; however, we were unable to obtain conclusive results using mRNA. This novel technique, combining albumin-based NBs and LoFreqUS offers a promising, efficient, targeted, and non-invasive solution for central nervous system gene therapy, potentially transforming the treatment landscape for neurological disorders.

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Slow Infusion of Recombinant Adeno-Associated Viruses into the Mouse Cerebrospinal Fluid Space

Cited by 8 publications

References 40 publications

Intrathecal Adeno-Associated Viral Vector-Mediated Gene Delivery for Adrenomyeloneuropathy

Intrathecal Adeno-Associated Viral Vector-Mediated Gene Delivery for Adrenomyeloneuropathy

Angiotensin-(1–7) reduces α-synuclein aggregation by enhancing autophagic activity in Parkinson’s disease

Intracranial Gene Delivery Mediated by Albumin-Based Nanobubbles and Low-Frequency Ultrasound

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