Evaluation of Intrathecal Routes of Administration for Adeno-Associated Viral Vectors in Large Animals
Open accessAbstract
Delivery of adeno-associated viral (AAV) vectors into the cerebrospinal fluid (CSF) can achieve gene transfer to cells throughout the brain and spinal cord, potentially making many neurological diseases tractable gene therapy targets. Identifying the optimal route of CSF access for intrathecal AAV delivery will be a critical step in translating this approach to clinical practice. We previously demonstrated that vector injection into the cisterna magna is a safe and effective method for intrathecal AAV delivery in nonhuman primates; however, this procedure is not commonly used in clinical practice. More routine methods of administration into the CSF are now being explored, including intracerebroventricular (ICV) injection and injection through a lumbar puncture. In this study, we compared ICV and intracisternal (IC) AAV administration in dogs. We also evaluated vector administration via lumbar puncture in nonhuman primates, with some animals placed in the Trendelenburg position after injection, a maneuver that has been suggested to improve cranial distribution of vector. In the dog study, ICV and IC vector administration resulted in similarly efficient transduction throughout the brain and spinal cord. However, animals in the ICV cohort developed encephalitis associated with a T-cell response to the transgene product, a phenomenon that was not observed in the IC cohort. In the nonhuman primate study, transduction efficiency was not improved by placing animals in the Trendelenburg position after injection. These findings illustrate important limitations of commonly used methods for CSF access in the context of AAV delivery, and will be important for informing the selection of a route of administration for first-in-human studies.
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In the study by Hinderer et al., comparison of intracisternal and intraventricular delivery of AAV9-GUSB to mucopolysaccharidosis-afflicted canines found that the intraventricular route led to inflammation and development of encephalitis.
“comparison of intracisternal and intraventricular delivery of AAV9-GUSB (1.8 × 1013 gc, 1 mL) to mucopolysaccharidosis-afflicted canines found that the intraventricular route lead to inflammation and development of encephalitis”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [95]
The Results report encephalitis in dogs given intraventricular AAV9-GFP, not AAV9-GUSB. The dog given intraventricular AAV9-GUSB had no clinical abnormalities or generalized encephalitis, although histology found a localized lesion with lymphocytic infiltration beside the needle track. The claim conflates the two experiments. (LLM, conf=0.91)
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Cites
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- Authors
- Hinderer, C., Bell, P., Katz, N., Vite, C. H., Louboutin, J.-P., Bote, E., Yu, H., Zhu, Y., Casal, M. L., Bagel, J., O'Donnell, P., Wang, P., Haskins, M. E., Goode, T., & Wilson, J. M.
- Affiliations
- University of Pennsylvania (US)
- University of the West Indies (TT)
- Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- ORCID
- Venue
- Human Gene Therapy
- Publisher
- SAGE Publications
- Published
- 2018-01
- Volume
- 29
- Issue
- 1
- Pages
- 15-24
- ISSN
- 1043-0342 (ISSN-L)
- 1557-7422
- PMC
- PMC5770082
- OpenAlex
- W2746920043
- Cited by
- 141
- References
- 18
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 36 · 2023: 16 · 2022: 19 · 2021: 16 · 2020: 18 · 2019: 9 · 2018: 10 · 2017: 1
- FWCI
- 6.88
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Human Gene Therapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- REGENXBIO
- National Institutes of Health (P40OD010939)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK054481)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- adeno-associated virus vectors, intrathecal gene delivery, cerebrospinal fluid, intracerebroventricular administration, intracisternal injection, lumbar puncture, Trendelenburg position, encephalitis, T cell response, transduction efficiency, dogs, non-human primates
- MeSH terms
- Dependovirus, Animals, Haplorhini, Central Nervous System Diseases, Dogs, Genetic Vectors, Injections, Spinal, Spinal Puncture, Genetic Therapy, Gene Transfer Techniques, Head-Down Tilt, Models, Animal, Infusions, Intraventricular
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