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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Hauser, MA; Robinson, A; Hartigan-O'Connor, D; Williams-Gregory, DA; Buskin, JN; Apone, S; Kirk, CJ; Hardy, S; Hauschka, SD; Chamberlain, JS

Published Date

  • July 2000

Published In

Volume / Issue

  • 2 / 1

Start / End Page

  • 16 - 25

PubMed ID

  • 10899824

Pubmed Central ID

  • 10899824

International Standard Serial Number (ISSN)

  • 1525-0016

Digital Object Identifier (DOI)

  • 10.1006/mthe.2000.0089

Language

  • eng

Conference Location

  • United States