The ependymal route for insulin-like growth factor-1 gene therapy in the brain
Open accessAbstract
I.c.v. administration of the peptide insulin-like growth factor-1 (IGF-1) has been shown to be an effective neuroprotective strategy in the brain of different animal models, a major advantage being the achievement of high concentrations of IGF-1 in the brain without altering serum levels of the peptide. In order to exploit this therapeutic approach further, we used high performance recombinant adenoviral (RAd) vectors expressing their transgene under the control of the potent mouse cytomegalovirus immediate early (mCMV) promoter, to transduce brain ependymal cells with high efficiency and to achieve effective release of transgenic IGF-1 into the cerebrospinal fluid (CSF). We constructed RAd vectors expressing either a chimeric green fluorescent protein fused to HSV-1 thymidine kinase (TK/GFP)(fus), or the cDNA encoding rat IGF-1, both driven by the mCMV promoter. The vectors were injected into the lateral ventricles of young rats and chimeric GFP expression in brain sections was assessed by fluorescence microscopy. The ependymal cell marker vimentin was detected by immunofluorescence and nuclei were labeled with the DNA dye 4',6-diamidino-2-phenylindole. Blood and CSF samples were drawn at different times post-vector injection. In all cerebral ventricles, vimentin immunoreactive cells of the ependyma were predominantly transduced by RAd-(TK/GFP)(fus), showing nuclear and cytoplasmic expression of the transgene. For tanycytes (TK/GFP)(fus) expression was evident in their cytoplasmic processes as they penetrated deep into the hypothalamic parenchyma. I.c.v. injection of RAd-IGF-1 induced high levels of IGF-1 in the CSF but not in serum. We conclude that the ependymal route constitutes an effective approach for implementing experimental IGF-1 gene therapy in the brain.
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Targeting the large cerebral ventricles (intraventricular route) in the frontal lobe is an easy surgical task and is commonly used to deliver drugs to the CNS.
“Targeting the large cerebral ventricles (intraventricular route) in the frontal lobe of the brain is an easy surgical task, and is commonly used to deliver drugs to the CNS.”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [85]
The Experimental Procedures (page not provided) describe stereotaxic injections into rats’ lateral ventricles, and the Discussion describes prior intraventricular delivery of IGF-1. These passages support use of the route to deliver a therapeutic agent, but do not establish that targeting ventricles in the frontal lobe is an easy surgical task or that the route is commonly used for drugs generally. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAfter intraventricular delivery the vector may be absorbed quickly into the chorionic villi and ependymal cells lining the ventricles.
“the vector may be absorbed quickly into the chorionic villi and ependymal cells lining the ventricles”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [85]
The Results (page unavailable) show that a vector injected into rat ventricles transduced ependymal cells lining the ventricles. The Discussion (page unavailable) mentions choroid transduction in an earlier mouse study, not uptake into “chorionic villi.” Neither passage establishes that the vector was absorbed quickly. (LLM, conf=0.85)
Experimental — accuracy not yet measured
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AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease
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- Authors
- Hereñú, C. B., Sonntag, W. E., Morel, G. R., Portiansky, E. L., & Goya, R. G.
- Affiliations
- Biochemistry Research Institute of La Plata (AR)
- University of Oklahoma Health Sciences Center (US)
- Universidad Nacional de La Plata (AR)
- Corresponding author
- Goya, R.G.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 163
- Issue
- 1
- Pages
- 442-447
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC2740751
- OpenAlex
- W2043914756
- Cited by
- 36
- References
- 30
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 3 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG-11370, R01AG029798-2, R01AG029798, P01AG011370)
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- insulin-like growth factor I, gene therapy, ependymal cells, adenoviral vector, intracerebroventricular administration, cerebrospinal fluid, neuroprotection, tanycytes, hypothalamus, HSV-1 thymidine kinase, vimentin, transduction efficiency
- MeSH terms
- Adenoviridae, Animals, Cell Nucleus, Cytoplasm, Ependyma, Female, Genetic Vectors, Humans, Hypothalamus, Injections, Intraventricular, Insulin-Like Growth Factor I, Molecular Biology, Promoter Regions, Genetic, Recombinant Fusion Proteins, Thymidine Kinase, Transduction, Genetic, Vimentin, Viral Proteins, Genetic Therapy, Gene Transfer Techniques, Transgenes, Lateral Ventricles, Green Fluorescent Proteins, Rats
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