Helper-Dependent Adenoviral Vector-Mediated Gene Transfer in Aged Rat Brain
| Autor: | Linglong Zou, Xiaoqing Yuan, Keyi Yang, Holly Lu, Heshan Zhou |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Male
Aging Indoles Genetic enhancement medicine.medical_treatment Genetic Vectors Gene Expression Enzyme-Linked Immunosorbent Assay Nerve Tissue Proteins Biology medicine.disease_cause Polymerase Chain Reaction Adenoviridae Cell Line Immunoenzyme Techniques Immune system Gene expression Genetics medicine Animals Vector (molecular biology) Molecular Biology fungi Genetic transfer Gene Transfer Techniques Brain food and beverages Galactosides Genetic Therapy beta-Galactosidase Rats Inbred F344 Rats Cell biology Cytokine nervous system Astrocytes Immunology Toxicity Molecular Medicine Microglia Helper Viruses |
| Zdroj: | Human Gene Therapy. 12:181-191 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/104303401750061249 |
| Popis: | Transfer of the neurotrophin gene into brain can attenuate age-related deficits such as neuronal atrophy and memory loss, but a suitable vector for this procedure has been lacking. The toxicity and immunogenicity of first-generation adenoviral vectors with E1 deletion (fgAdv) prohibit the application of gene transfer in the majority of central nervous system disorders. Here, we report less toxic and persistent gene expression mediated by helper-dependent adenovirus (hdAdv) in aged rat brain. After intrahippocampal or intraventricular inoculation of the vector, transgene expression was monitored by X-Gal staining and compared with fgAdv-mediated expression. Host inflammatory and immune responses against these vectors were evaluated by immunohistochemical detection of microglia, astrocytes, and infiltrating macrophages, as well as by enzyme-linked immunosorbent assay of cytokines TNF-alpha and IL-1beta. Transgene expression mediated by hdAdv persisted for more than 183 days regardless of inoculation site, as compared with 33 and 66 days for fgAdv-mediated expression after intraventricular and intrahippocampal inoculation, respectively. Inoculation with hdAdv was also associated with reduced numbers of activated microglial cells, astrocytes, and infiltrating macrophages in brain tissue. Secretion of the proinflammatory cytokines TNF-alpha and IL-1beta was minimal after hdAdv but not after fgAdv inoculation. These findings indicate that hdAdv would provide a safe and effective means to transfer therapeutic genes into aged brain. |
| Databáze: | OpenAIRE |
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