Glymphatic fluid transport controls paravascular clearance of AAV vectors from the brain
Open accessAbstract
Adeno-associated viruses (AAV) are currently being evaluated in clinical trials for gene therapy of CNS disorders. However, host factors that influence the spread, clearance, and transduction efficiency of AAV vectors in the brain are not well understood. Recent studies have demonstrated that fluid flow mediated by aquaporin-4 (AQP4) channels located on astroglial end feet is essential for exchange of solutes between interstitial and cerebrospinal fluid. This phenomenon, which is essential for interstitial clearance of solutes from the CNS, has been termed glial-associated lymphatic transport or glymphatic transport. In the current study, we demonstrate that glymphatic transport profoundly affects various aspects of AAV gene transfer in the CNS. Altered localization of AQP4 in aged mouse brains correlated with significantly increased retention of AAV vectors in the parenchyma and reduced systemic leakage following ventricular administration. We observed a similar increase in AAV retention and transgene expression upon i.c.v. administration in AQP4 –/– mice. Consistent with this observation, fluorophore-labeled AAV vectors showed markedly reduced flux from the ventricles of AQP4 –/– mice compared with WT mice. These results were further corroborated by reduced AAV clearance from the AQP4-null brain, as demonstrated by reduced transgene expression and vector genome accumulation in systemic organs. We postulate that deregulation of glymphatic transport in aged and diseased brains could markedly affect the parenchymal spread, clearance, and gene transfer efficiency of AAV vectors. Assessment of biomarkers that report the kinetics of CSF flux in prospective gene therapy patients might inform variable treatment outcomes and guide future clinical trial design.
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Leveraging convective CSF flow along perivascular spaces could overcome diffusional limitations and provide a direct mechanism for transport to deep brain structures.
“Leveraging convective CSF flow along perivascular spaces could overcome diffusional limitations and provide a direct mechanism for transport to deep brain structures [13–15].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [14]
The Introduction describes convective CSF currents along paravascular compartments, and the Results report widespread AAV distribution after intra-CSF administration in wild-type mice but more localized distribution when AQP4-mediated flow is impaired. The paper does not establish that this flow overcomes diffusional limitations or provides a direct transport route specifically to deep brain structures; its observations of AAV in the thalamus and hypothalamus do not establish that mechanism. (LLM, conf=0.84)
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The Glymphatic System: A Review
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MHC class I and II expression and induction in oligodendrocytes varies with age
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RETRACTED: Exploring the role of astrocytic dysfunction and AQP4 in depression
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Chronic Intraventricular Cannulation for the Study of Glymphatic Transport
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Glymphatic Inhibition Exacerbates Tau Propagation in an Alzheimer’s Disease ModelPreprint
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DETERMINANTS OF AAV TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER
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Preclinical Evaluation of Neuraxial Drugs for Safety
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CNS targeted AAV gene therapies: Recent advances and clinical insights
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- Authors
- Murlidharan, G., Crowther, A., Reardon, R. A., Song, J., & Asokan, A.
- Affiliations
- Curriculum in Genetics and Molecular Biology,
- Neurobiology Curriculum,
- Gene Therapy Center,
- Department of Pharmacology,
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Asokan, Aravind
- Venue
- JCI Insight
- Published
- 2016-09-08
- Volume
- 1
- Issue
- 14
- Pages
- e88034-e88034
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC5033923
- OpenAlex
- W2509605723
- Cited by
- 72
- References
- 38
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 13 · 2021: 5 · 2020: 3 · 2019: 8 · 2018: 7 · 2017: 7
- FWCI
- 5.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (P30-AI- 027767)
- Gillings School of Public Health
- University of North Carolina at Chapel Hill
- University of California, San Francisco
- National Heart, Lung, and Blood Institute (P01HL112761, R01HL089221)
- National Cancer Institute (P30CA016086)
- National Institute of Allergy and Infectious Diseases (P30AI027767)
- National Institute of Environmental Health Sciences (P30ES010126)
- 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 › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- glymphatic system, adeno-associated virus vectors, aquaporin-4, cerebrospinal fluid flow, brain aging, astrocytes, transgene expression
- MeSH terms
- Dependovirus, Animals, Biological Transport, Brain, Genetic Vectors, Mice, Inbred C57BL, Transduction, Genetic, Genetic Therapy, Mice, Knockout, Mice, Aquaporin 4
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