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A small regulatory element from chromosome 19 enhances liver-specific gene expression.

Publication ,  Journal Article
Li, C; Hirsch, M; Carter, P; Asokan, A; Zhou, X; Wu, Z; Samulski, RJ
Published in: Gene Ther
January 2009

Tissue-specific promoters for gene therapy are typically too big for adeno-associated virus (AAV) vectors; thus, the exploration of small effective non-viral regulatory elements is of particular interest. Wild-type AAV can specifically integrate into a region on human chromosome 19 termed AAVS1. Earlier work has determined that a 347 bp fragment (Chr19) of AAVS1 has promoter and transcriptional enhancer activities. In this study, we further characterized this genetic regulation and investigated its application to AAV gene therapy in vitro and in vivo. The Chr19 347 bp fragment was dissected into three regulatory elements in human embryonic kidney cells: (i) TATA-independent promoter activity distributed throughout the fragment regardless of orientation, (ii) an orientation-dependent insulator function near the 5' end and (iii) a 107 bp enhancer region near the 3' end. The small enhancer region, coupled to the mini-CMV promoter, was used to drive the expression of several reporters following transduction by AAV2. In vivo data demonstrated enhanced transgene expression from the Chr19-mini-CMV promoter cassette after tail vein injection primarily in the liver at levels comparable to the chicken beta-actin promoter and higher than the liver-specific TTR promoter (>2-fold). However, we did not observe this increase after muscle injection, suggesting tissue-specific enhancement. All of the results support identification of a small DNA fragment (347 bp) from AAV Chr19 integration site capable of providing efficient and enhanced liver-specific transcription when used in recombinant AAV vectors.

Duke Scholars

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Published In

Gene Ther

DOI

EISSN

1476-5462

Publication Date

January 2009

Volume

16

Issue

1

Start / End Page

43 / 51

Location

England

Related Subject Headings

  • Virus Integration
  • Transgenes
  • Transduction, Genetic
  • Transcription, Genetic
  • Regulatory Sequences, Nucleic Acid
  • Promoter Regions, Genetic
  • Muscles
  • Mice, Inbred BALB C
  • Mice
  • Luminescence
 

Citation

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Li, C., Hirsch, M., Carter, P., Asokan, A., Zhou, X., Wu, Z., & Samulski, R. J. (2009). A small regulatory element from chromosome 19 enhances liver-specific gene expression. Gene Ther, 16(1), 43–51. https://doi.org/10.1038/gt.2008.134
Li, C., M. Hirsch, P. Carter, A. Asokan, X. Zhou, Z. Wu, and R. J. Samulski. “A small regulatory element from chromosome 19 enhances liver-specific gene expression.Gene Ther 16, no. 1 (January 2009): 43–51. https://doi.org/10.1038/gt.2008.134.
Li C, Hirsch M, Carter P, Asokan A, Zhou X, Wu Z, et al. A small regulatory element from chromosome 19 enhances liver-specific gene expression. Gene Ther. 2009 Jan;16(1):43–51.
Li, C., et al. “A small regulatory element from chromosome 19 enhances liver-specific gene expression.Gene Ther, vol. 16, no. 1, Jan. 2009, pp. 43–51. Pubmed, doi:10.1038/gt.2008.134.
Li C, Hirsch M, Carter P, Asokan A, Zhou X, Wu Z, Samulski RJ. A small regulatory element from chromosome 19 enhances liver-specific gene expression. Gene Ther. 2009 Jan;16(1):43–51.

Published In

Gene Ther

DOI

EISSN

1476-5462

Publication Date

January 2009

Volume

16

Issue

1

Start / End Page

43 / 51

Location

England

Related Subject Headings

  • Virus Integration
  • Transgenes
  • Transduction, Genetic
  • Transcription, Genetic
  • Regulatory Sequences, Nucleic Acid
  • Promoter Regions, Genetic
  • Muscles
  • Mice, Inbred BALB C
  • Mice
  • Luminescence