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Analysis of muscle creatine kinase regulatory elements in recombinant adenoviral vectors.

Publication ,  Journal Article
Hauser, MA; Robinson, A; Hartigan-O'Connor, D; Williams-Gregory, DA; Buskin, JN; Apone, S; Kirk, CJ; Hardy, S; Hauschka, SD; Chamberlain, JS
Published in: Mol Ther
July 2000

Adenoviral gene transfer holds promise for gene therapy, but effective transduction of a large and distributed tissue such as muscle will almost certainly require systemic delivery. In this context, the use of muscle-specific regulatory elements such as the muscle creatine kinase (MCK) promoter and enhancer will avoid potentially harmful ectopic expression of transgenes. We describe here the development and testing of adenoviral vectors containing small, striated muscle-specific, highly active MCK expression cassettes. One of these regulatory elements (CK6) is less than 600 bp in length and is 12% as active as the CMV promoter/enhancer in muscle. A recombinant adenoviral vector containing this regulatory element retains very high muscle specificity, expressing 600-fold higher levels of transgene in muscle than in liver. Muscle-specific regulatory elements may also increase persistence of transduced muscle cells. Adenoviral transduction of dendritic cells has been shown to stimulate cytotoxic T-lymphocyte (CTL) responses directed against transgene epitopes. We show that human dendritic cells infected in vitro with MCK-containing adenoviruses do not express significant levels of transgene. Furthermore, while adenoviral vectors containing nonspecific promoters are normally cleared from muscle tissue within 1 month, we show that MCK-containing vectors express significant levels of transgene 4 months after intramuscular injection.

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Published In

Mol Ther

DOI

ISSN

1525-0016

Publication Date

July 2000

Volume

2

Issue

1

Start / End Page

16 / 25

Location

United States

Related Subject Headings

  • beta-Galactosidase
  • Transgenes
  • Time Factors
  • Regulatory Sequences, Nucleic Acid
  • Promoter Regions, Genetic
  • Mutagenesis
  • Muscles
  • Molecular Sequence Data
  • Models, Genetic
  • Mice, Inbred C57BL
 

Citation

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Hauser, M. A., Robinson, A., Hartigan-O’Connor, D., Williams-Gregory, D. A., Buskin, J. N., Apone, S., … Chamberlain, J. S. (2000). Analysis of muscle creatine kinase regulatory elements in recombinant adenoviral vectors. Mol Ther, 2(1), 16–25. https://doi.org/10.1006/mthe.2000.0089
Hauser, M. A., A. Robinson, D. Hartigan-O’Connor, D. A. Williams-Gregory, J. N. Buskin, S. Apone, C. J. Kirk, S. Hardy, S. D. Hauschka, and J. S. Chamberlain. “Analysis of muscle creatine kinase regulatory elements in recombinant adenoviral vectors.Mol Ther 2, no. 1 (July 2000): 16–25. https://doi.org/10.1006/mthe.2000.0089.
Hauser MA, Robinson A, Hartigan-O’Connor D, Williams-Gregory DA, Buskin JN, Apone S, et al. Analysis of muscle creatine kinase regulatory elements in recombinant adenoviral vectors. Mol Ther. 2000 Jul;2(1):16–25.
Hauser, M. A., et al. “Analysis of muscle creatine kinase regulatory elements in recombinant adenoviral vectors.Mol Ther, vol. 2, no. 1, July 2000, pp. 16–25. Pubmed, doi:10.1006/mthe.2000.0089.
Hauser MA, Robinson A, Hartigan-O’Connor D, Williams-Gregory DA, Buskin JN, Apone S, Kirk CJ, Hardy S, Hauschka SD, Chamberlain JS. Analysis of muscle creatine kinase regulatory elements in recombinant adenoviral vectors. Mol Ther. 2000 Jul;2(1):16–25.
Journal cover image

Published In

Mol Ther

DOI

ISSN

1525-0016

Publication Date

July 2000

Volume

2

Issue

1

Start / End Page

16 / 25

Location

United States

Related Subject Headings

  • beta-Galactosidase
  • Transgenes
  • Time Factors
  • Regulatory Sequences, Nucleic Acid
  • Promoter Regions, Genetic
  • Mutagenesis
  • Muscles
  • Molecular Sequence Data
  • Models, Genetic
  • Mice, Inbred C57BL