Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis

Yang, Yiping; Nunes, Frederick A.; Berencsi, Klára; Gönczöl, Éva; Engelhardt, John F.; Wilson, James M.

doi:10.1038/ng0794-362

Cited by 448 publications

(297 citation statements)

References 28 publications

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“…First, direct toxicity to myofibers may result from either exposure to AdV capsid proteins 17,18 delivered in the initial inoculum or interference with normal cellular function by factors such as low-grade de novo expression of adenoviral genes. [19][20][21] Second, host immune responses directed against AdV-infected cells and attendant elimination of transduced myofibers can lead to adverse effects on force-generating capacity. 11,12 Third, the use of germ cell correction of the genetic abnormality to prevent disease onset in transgenic animals differs substantially from the anticipated clinical scenario, which would involve treating individuals with established disease of varying degrees of severity.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice

et al. 1998

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Duchenne muscular dystrophy (DMD) and murine X-linked logy and muscle weakness. The main findings are as folmuscular dystrophy (mdx) are both due to absence of the lows: (1) acute myofiber toxicity and gene transfer subsarcolemmal protein dystrophin. Recombinant adenoefficiency are both AdV dose-dependent, such that the virus vectors (AdV) are considered a promising means for therapeutic margin of safety is fairly narrow; (2) immunodelivering a functional dystrophin gene to muscle. Howsuppressive therapy (FK506) prevents immune-mediated ever, the usefulness of AdV for this purpose is limited by elimination of dystrophin-positive fibers but not the dosevector toxicity as well as immune-mediated elimination of dependent toxic effects; (3) at the optimal vector dosage infected fibers. In addition, studies to date of AdV-mediated and with effective immunosuppression, AdV-mediated dysdystrophin gene transfer have either failed to examine trophin minigene transfer is capable of alleviating the loss effects on muscle strength or been performed in immunoof force-generating capacity as well as histopathological logically immature neonatal animals with little baseline evidence of disease progression normally seen in adult abnormality of force-generating capacity. In the present mdx muscles over a 2-month period. These findings have study, AdV-mediated dystrophin gene transfer was perforimportant implications for the eventual application of AdVmed in adult mdx mice with pre-existent dystrophic pathomediated dystrophin gene transfer in DMD patients.

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Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice

et al. 1998

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“…16 However, adenoviruses show inherent immunological problems, 17 resulting in reduction of gene expression on repeated application. Alterations in the adenovirus sero-type, 18 blocking antibodies to the CD40 antigen 19 and increasing deletions of the viral genome 20 have begun to address this problem. Both preclinical studies in primates and cotton rats 21,22 and clinical trials in man show adenoviruses are capable of producing an acute T cell-mediated inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

The extra- and intracellular barriers to lipid and adenovirus-mediated pulmonary gene transfer in native sheep airway epithelium

Kitson¹,

Ángel²,

Judd³

et al. 1999

Gene Ther

123

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Gene transfer to the respiratory epithelium is currently apical membrane represented a significant barrier to both suboptimal and may be helped by the identification of limitagents. Adenovirus-mediated expression could be signifiing biological barriers. We have, therefore, developed an cantly augmented by increasing contact time or by preex vivo model which retains many of the characteristics of treatment of tissues with a nominally calcium-free medium. in vivo native airways including mucociliary clearance,The presence of these extracellular and plasma membrane mucus coverage and an intact cellular structure. Using this barriers appeared to be the key parameters responsible for model we have demonstrated several barriers to gene the approximately three log difference in gene expression transfer. Liposome-mediated gene transfer was inhibited found in vitro compared with our ex vivo model. Cytoskeleby normal mucus, with removal of this layer increasing tal elements and the cell cycle also influenced in vitro gene expression approximately 25-fold. In addition both lipotransfer, and represent further barriers which need to be some and adenovirus were inhibited by CF sputum. The overcome.

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“…To circumvent vector-mediated cytotoxicity several new types of vectors have been developed including those with deletions in regions E2 or E4 24,26,27,29,38 and helper-dependent Ads. 30,[39][40][41][42][43] To minimize difficulties associated with contaminating helper virus, a Cre/loxP helper-dependent system was developed.…”

Section: Discussionmentioning

confidence: 99%

“…However, propagation of these vectors is complicated by the further requirement for E2 and E4 protein expression in the complementing host cells, and improved tolerance has not yet been demonstrated. [22][23][24][25][26][27][28][29] Recently, a system has been developed for the production of helper-dependent Ad vectors (hdAd) that are deleted for most adenovirus coding sequences. 30 In this system, the helper virus contains a packaging signal flanked by loxP sites.…”

Section: Introductionmentioning

confidence: 99%

Helper-dependent adenovirus vectors: their use as a gene delivery system to neurons

et al. 2000

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Recombinant adenovirus vectors have provided a major advance in gene delivery systems for post-mitotic neurons. However, the use of these first generation vectors has been limited due to the onset of virally mediated effects on cellular function and viability. In the present study we have used primary cultures of cerebellar granule neurons to examine the efficacy and cytotoxic effects of a helper-dependent adenovirus vector (hdAd) in comparison with a first generation vector. Our results demonstrate that the hdAd system provides equally efficient infectivity with significantly reduced toxicity in comparison to first generation vectors. Neurons transduced with a high titre of a first generation vector exhibited a time-dependent shut down in global protein synthesis and impaired physiological function as demonstrated by a

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Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis

Cited by 448 publications

References 28 publications

Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice

Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice

The extra- and intracellular barriers to lipid and adenovirus-mediated pulmonary gene transfer in native sheep airway epithelium

Helper-dependent adenovirus vectors: their use as a gene delivery system to neurons

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