Prolonged Transgene Expression Mediated by a Helper-Dependent Adenoviral Vector (hdAd) in the Central Nervous System

Zou, Linglong; Zhou, Huiyun; Pastore, Lucio; Yang, Kuo-Hsin

doi:10.1006/mthe.2000.0104

Cited by 78 publications

(54 citation statements)

References 37 publications

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“…However, second-generation adenoviral vectors, as used in the present study, are less immunogenic and promote more stable and long-term transgene expression than conventional first-generation vectors (Thomas et al, 2000;Zou et al, 2000). In the present study, there was negligible cellular damage (other than mechanical tissue disruption) and minimal astrocytic and microglial reactivity after adenoviral administration suggesting that the vector had minimal, cytotoxicity and immunogenicity.…”

Section: Ad-apoementioning

confidence: 53%

APOE ε3 Gene Transfer Attenuates Brain Damage after Experimental Stroke

McColl

McGregor

Wong

et al. 2006

J Cereb Blood Flow Metab

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Apolipoprotein E (apoE, protein; APOE, gene) is the major lipid-transport protein in the brain and plays an important role in modulating the outcome and regenerative processes after acute brain injury. The aim of the present study was to determine if gene transfer of the e3 form of APOE improves outcome in a murine model of transient focal cerebral ischaemia. Mice received an intrastriatal injection of vehicle, a second-generation adenoviral vector containing the green fluorescent protein gene (Ad-GFP) or a vector containing the APOE e3 gene (Ad-APOE) 3 days before 60 mins focal ischaemia. Green fluorescent protein expression was observed in cells throughout the striatum and subcortical white matter indicating successful gene transfer and expression. ApoE levels in the brain were significantly increased after Ad-APOE compared with Ad-GFP or vehicle treatment. Ad-APOE treatment reduced the volume of ischaemic damage by 50% compared with Ad-GFP or vehicle treatment (1363 versus 2964 versus 2765 mm 3 ). The extent of postischaemic apoE immunoreactivity was enhanced in Ad-APOE compared with Ad-GFP or vehicle treated mice. These results show the ability of APOE gene transfer to markedly improve outcome after cerebral ischaemia and suggest that modulating apoE levels may be a potential strategy in human stroke therapy.

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Section: Ad-apoementioning

confidence: 53%

APOE ε3 Gene Transfer Attenuates Brain Damage after Experimental Stroke

McColl

McGregor

Wong

et al. 2006

J Cereb Blood Flow Metab

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show abstract

“…In naïve rats not exposed previously to adenovirus, transgene expression from adenoviral vectors is stable for up to 13 months (Byrnes et al, 1995;Geddes et al, 1997;Kajiwara et al, 1997;Ideguchi et al, 2000;Thomas et al, 2000b;Zou et al, 2000;Amalfitano et al, 2002;Glover et al, 2003). However, systemic immunization of animals injected previously with adenovirus into the CNS with first-generation adenoviral vectors leads to immune responses in the CNS that substantially reduce and, in some cases, eliminate transgene expression from the brain (Byrnes et al, 1995;Byrnes et al, 1996a;Byrnes et al, 1996b;Wood et al, 1996;Kajiwara et al, 1997;Thomas et al, 2000;Zermansky et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…<1 month) results from the use of very high titers that are cytotoxic because they stimulate a strong innate immune response (Thomas et al, 2001a), the injection of vectors into the brain ventricles, which primes the systemic immune system (Lowenstein, 2002;Tada et al, 2005), or contaminated vector preparations. However, if injectionskeep the amount of injected vectors to ~10 7 iu, are delivered carefully into the brain parenchyma, and vector preparations are devoid of lipopolysaccharide and replication competent adenovirus, expression lasts between 6-18 months (Byrnes et al, 1995;Geddes et al, 1997;Kajiwara et al, 1997;Ideguchi et al, 2000;Thomas et al, 2000b;Zou et al, 2000;Amalfitano et al, 2002;Glover et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

et al. 2006

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First-generation adenovirus can be engineered with powerful promoters to drive expression of therapeutic transgenes. Numerous clinical trials for glioblastoma multiforme using first generation adenoviral vectors have either been performed or are ongoing, including an ongoing, Phase III, multicenter trial in Europe and Israel (Ark Therapeutics, Inc.). Although in the absence of antiadenovirus immune responses expression in the brain lasts 6-18 months, systemic infection with adenovirus induces immune responses that inhibit dramatically therapeutic transgene expression from first generation adenoviral vectors, thus, potentially compromising therapeutic efficacy. Here, we show evidence of an immunization threshold for the dose that generates an immune response strong enough to eliminate transgene expression from the CNS. For the systemic immunization to eliminate transgene expression from the brain, ≥1 × 10 7 infectious units (iu) of adenovirus need to be used as immunogen. Furthermore, this immune response eliminates >90% of transgene expression from 1 × 10 7 -1 × 10³ iu of vector injected into the striatum 60 days earlier. Importantly, elimination of transgene expression is independent of the nature of the promoter that drives transgene expression and is accompanied by brain infiltration of CD8 + T cells and macrophages. In conclusion, once the threshold for systemic immunization (i.e. 1 × 10 7 iu) is crossed, the immune response eliminates transgene expression by >90% even from brains that receive as little as 1000 iu of adenoviral vectors, independently of the type of promoter that drives expression.

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“…Despite the immunoprotection of the CNS, results with first-generation adenovirus show a decrease in the expression of the transgene 2 months after transduction, correlating with the disappearance of the adenoviral DNA. 108 Acute loss of transduced cells and chronic inflammation could account for this decline, mainly at high doses. 109 On the contrary, gutless adenovirus expression can be detected in the CNS 1 year after striatal injections.…”

Section: Gutless Adenovirus and Immune Responsementioning

confidence: 99%

Gutless adenovirus: last-generation adenovirus for gene therapy

2005

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Last-generation adenovirus vectors, also called helper-dependent or gutless adenovirus, are very attractive for gene therapy because the associated in vivo immune response is highly reduced compared to first-and second-generation adenovirus vectors, while maintaining high transduction efficiency and tropism. Nowadays, gutless adenovirus is administered in different organs, such as the liver, muscle or the central nervous system achieving high-level and long-term transgene expression in rodents and primates. However, as devoid of all viral coding regions, gutless vectors require viral proteins supplied in trans by a helper virus. To remove contamination by a helper virus from the final preparation, different systems based on the excision of the helper-packaging signal have been generated. Among them, Cre-loxP system is mostly used, although contamination levels still are 0.1-1% too high to be used in clinical trials. Recently developed strategies to avoid/reduce helper contamination were reviewed. Gene Therapy (2005) 12, S18-S27.

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Prolonged Transgene Expression Mediated by a Helper-Dependent Adenoviral Vector (hdAd) in the Central Nervous System

Cited by 78 publications

References 37 publications

APOE ε3 Gene Transfer Attenuates Brain Damage after Experimental Stroke

APOE ε3 Gene Transfer Attenuates Brain Damage after Experimental Stroke

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

Gutless adenovirus: last-generation adenovirus for gene therapy

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