<i>In Vivo</i> Expression of Full-Length Human Dystrophin from Adenoviral Vectors Deleted of All Viral Genes

Haecker, Sarah Ehlen; Stedman, Hansell H.; Balice-Gordon, Rita J.; Smith, Deryan; Greelish, James P.; Mitchell, Matthew D.; Wells, Anne M.; Sweeney, H. Lee; Wilson, James M.

doi:10.1089/hum.1996.7.15-1907

Cited by 140 publications

(87 citation statements)

References 24 publications

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“…33 A potential role for E4 genes in target organ toxicity after AdV administration is suggested by a recent report that the early hepatotoxicity seen after E1-deleted AdV delivery to liver is reduced by using a doubly (E1 + E4)-deleted vector. 34 Furthermore, AdV that are deleted of all viral coding sequences have recently been developed, 35,36 which have the additional advantage of being able to accommodate the more efficacious full-length dystrophin gene. The availability of vectors with a higher therapeutic index, in turn, could allow for higher AdV dosages to be employed, as well as repeated vector administration (under immunosuppression) into the same muscle.…”

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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“…The development of systems for the generation of helper-dependent Ad vectors (hdAd) which are deleted for most if not all viral coding sequences, [32][33][34][35][36][37][38][39] has allowed production of hdAd which can provide long-term, highlevel transgene expression, [40][41][42] and which result in substantially reduced inflammatory and cellular immune responses. [41][42][43] However, as expected, deletion of all Ad coding sequences does not overcome the humoral immune response, and the resultant neutralizing antibodies (JL Bramson, RJP and FLG, unpublished results), impair the effectiveness of hdAd vector readministration.…”

Section: Introductionmentioning

confidence: 99%

Use of helper-dependent adenoviral vectors of alternative serotypes permits repeat vector administration

1999

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We have developed a new helper adenovirus (Ad) based expression in mouse liver after intravenous injection of the on serotype 2, Ad2LC8cCARP, for use in the Cre/loxP sysAd2-based hdAd showed that the vector could efficiently tem (Parks et al. Proc Natl Acad Sci USA, 1996; 93: transduce the liver, and produce high levels of a foreign 13565-13570) to generate Ad vectors deleted of all protein transgene, similar to those expressed by the hdAd genercoding sequences (helper-dependent Ad vectors (hdAd) ).ated with the Ad5 helper virus. Mice immunized with hdAd2 A comparison of Ad2LC8cCARP and our original helper produced Ad2-neutralizing antibodies, which did not crossvirus (based on serotype 5, Ad5LC8cluc) showed that the react with hdAd5. To determine if successful repeat Ad two helper viruses amplified hdAd with a similar efficiency, vector administration could be achieved by sequential use and resulted in a similar yield and purity after large-scale of alternative Ad serotypes, we injected mice with hdAd2 preparation of vector. In vitro, the resulting hdAd2 had a (hSEAP) followed 3 months later by a lacZ-expressing similar transduction efficiency and expression kinetics of hdAd of either the same or different serotype. Repeated transgene (␤-gal) as the hdAd5. An important feature of administration of hdAd2 resulted in a 30-to 100-fold the helper-dependent system is that all virion components, reduction in transgene expression compared with naive except the virion DNA, derive from the helper virus. Conseanimals. In contrast, no decrease in transgene expression quently, vectors produced with help from Ad2LC8cCARP was observed when the second vector was of a different were not neutralized by antibodies against Ad5, and vecserotype. These results demonstrate that effective vector tors produced with Ad5 helper were resistant to neutralizreadministration can be achieved by the sequential use of ing antibodies against Ad2. Analysis of transgene hdAds based on alternative serotypes.

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“…One goal of cancer gene therapy is the development of gene delivery tools with lowered immunogenicity. While the construction of some viral vectors with reduced immunogenicity have been reported (Fisher et al, 1996;Haecker et al, 1996;Kochanek et al, 1996;Kumar-Singh and Chamberlain, 1996;Morral et al, 1999), preparation of these vectors is difficult because the virus is composed of several kinds of large molecules.…”

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confidence: 99%

Fusion of HIV-1 Tat protein transduction domain to poly-lysine as a new DNA delivery tool

et al. 2004

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Effective gene therapy depends on the efficient transfer of therapeutic genes to target cells. None of the current technologies, however, satisfy all of the requirements necessary for gene therapy, because the plasma and nuclear membranes of mammalian cells are tight barriers against gene transfer using synthetic delivery systems. The protein transduction domain (PTD) of human immunodeficiency virus type 1 (HIV-1) Tat protein greatly facilitates protein transfer via membrane destabilisation. We synthesised polylysine peptides containing Tat PTD (TAT-pK), or other sequences, and investigated their potential as agents for gene transfer. The synthesised polypeptide TAT-pK retains DNA binding function and mediates delivery of a reporter gene to cultured cells. RGD motif binds with low affinity to alpha integrins which induce cell activation. Two control polypeptides, GGG-pK and RGD-pK, were synthesised and tested, but their gene transfer abilities were weaker than those of TAT-pK. TAT-pK-mediated gene transfer was enhanced in the presence of chloroquine or ammonium chloride, to a greater extent than that of cationic lipid-mediated gene transfer in most cancer cell lines tested. These data suggest that TAT-pK may be a potent candidate delivery vehicle that promotes gene transfer, dependent on the endocytic pathway. We conclude that the TAT-pK/DNA complex is useful as a minimal unit to package therapeutic genes and to transduce them into mammalian cells.

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In Vivo Expression of Full-Length Human Dystrophin from Adenoviral Vectors Deleted of All Viral Genes

Cited by 140 publications

References 24 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

Use of helper-dependent adenoviral vectors of alternative serotypes permits repeat vector administration

Fusion of HIV-1 Tat protein transduction domain to poly-lysine as a new DNA delivery tool

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