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Cited by 85Virus-based gene therapy researchCerebrospinal fluid and hydrocephalusRNA Interference and Gene Delivery

Kinetics and MR-Based Monitoring of AAV9 Vector Delivery into Cerebrospinal Fluid of Nonhuman Primates

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Ohno, Kousaku, Samaranch, Lluis, Hadaczek, Piotr, Bringas, John R., Allen, Philip C., Sudhakar, Vivek, Stockinger, Diane E., Snieckus, Christopher +8 more·2019·Molecular Therapy - Methods & Clinical Development
DOI 10.1016/j.omtm.2018.12.001PMC PMC6330508
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Abstract

Here we evaluated the utility of MRI to monitor intrathecal infusions in nonhuman primates. Adeno-associated virus (AAV) spiked with gadoteridol, a gadolinium-based MRI contrast agent, enabled real-time visualization of infusions delivered either via cerebromedullary cistern, lumbar, cerebromedullary and lumbar, or intracerebroventricular infusion. The kinetics of vector clearance from the cerebrospinal fluid (CSF) were analyzed. Our results highlight the value of MRI in optimizing the delivery of infusate into CSF. In particular, MRI revealed differential patterns of infusate distribution depending on the route of delivery. Gadoteridol coverage analysis showed that cerebellomedullary cistern delivery was a reliable and effective route of injection, achieving broad infusate distribution in the brain and spinal cord, and was even greater when combined with lumbar injection. In contrast, intracerebroventricular injection resulted in strong cortical coverage but little spinal distribution. Lumbar injection alone led to the distribution of MRI contrast agent mainly in the spinal cord with little cortical coverage, but this delivery route was unreliable. Similarly, vector clearance analysis showed differences between different routes of delivery. Overall, our data support the value of monitoring CSF injections to dissect different patterns of gadoteridol distribution based on the route of intrathecal administration.

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  • Intra-cisterna magna injection and lumbar puncture have shown a wider biodistribution of AAV9 within the brain and spinal cord, despite procedural risks and moderate toxicity.

    “Yet, intra-cisterna magna injection and lumbar puncture have shown a wider biodistribution of AAV9 within the brain and spinal cord, despite the procedural risks and moderate toxicity linked to these methods [82].”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [82]

    The Discussion reports broad brain and spinal-cord distribution after cisterna magna delivery, with still greater coverage when combined with lumbar injection. It says lumbar injection alone distributed the tracer primarily in the spinal cord, with little brain coverage. The Introduction describes procedural risks of lumbar puncture, but the Results report no adverse events in treated animals and do not establish moderate toxicity. (LLM, conf=0.90)

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Authors
Ohno, K., Samaranch, L., Hadaczek, P., Bringas, J. R., Allen, P. C., Sudhakar, V., Stockinger, D. E., Snieckus, C., Campagna, M. V., San Sebastian, W., Naidoo, J., Chen, H., Forsayeth, J., Salegio, E. A., Hwa, G. G. C., & Bankiewicz, K. S.
Affiliations
  • University of California, San Francisco (US)
  • Virovek (United States) (US)
Corresponding author
Bankiewicz, Krystof S.
ORCID
Venue
Molecular Therapy - Methods & Clinical Development
Publisher
Elsevier BV
Published
2019-06
Volume
13
Pages
47-54
ISSN
2329-0501 (ISSN-L)
DOI
10.1016/j.omtm.2018.12.001
PMC
PMC6330508
OpenAlex
W2903881397
Cited by
85
References
4
Citations by year
2026: 9 · 2025: 10 · 2024: 26 · 2023: 12 · 2022: 4 · 2021: 11 · 2020: 11 · 2019: 2
FWCI
3.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy — Methods & Clinical Development (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
Kinetics Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
AAV9, intrathecal gene delivery, cerebrospinal fluid, gadoteridol, gadolinium-based MRI contrast agents, lumbar injection, intracerebroventricular administration, non-human primates

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