Hypoxia as a target for tissue specific gene therapy

J Control Release. 2013 Dec 10;172(2):484-94. doi: 10.1016/j.jconrel.2013.05.021. Epub 2013 Jun 3.


Hypoxia is a hallmark of various ischemic diseases such as ischemic heart disease, ischemic limb, ischemic stroke, and solid tumors. Gene therapies for these diseases have been developed with various therapeutic genes including growth factors, anti-apoptotic genes, and toxins. However, non-specific expression of these therapeutic genes may induce dangerous side effects in the normal tissues. To avoid the side effects, gene expression should be tightly regulated in an oxygen concentration dependent manner. The hypoxia inducible promoters and enhancers have been evaluated as a transcriptional regulation tool for hypoxia inducible gene therapy. The hypoxia inducible UTRs were also used in gene therapy for spinal cord injury as a translational regulation strategy. In addition to transcriptional and translational regulations, post-translational regulation strategies have been developed using the HIF-1α ODD domain. Hypoxia inducible transcriptional, translational, and post-translational regulations are useful for tissue specific gene therapy of ischemic diseases. In this review, hypoxia inducible gene expression systems are discussed and their applications are introduced.

Keywords: ARNT; ATF-4; BBB; Basso, Beattie, and Bresnahan; CYP2B6; Cygb; DBD; DNA binding domain; ERE; Epo; GAPDH; GLP-1; Gene regulation; Gene therapy; Gpx-1; HIF-1; HRE; Hypoxia; IREs; MT; ODD; Oxygen dependent degradation; PGK-1; PHDs; Promoter; RCC; REDD1; ROS; SHP-1; SP-1; SSP; SV40; Src homology domain-2 containing tyrosine phosphatase-1; TAD; TH; TSTA; UPR; UTR; Untranslated region; VEGF; X-linked inhibitor of apoptosis protein; XIAP; activating transcription factor-4; aryl hydrocarbon receptor nuclear translocator; bHLH; basic helix-loop-helix; cFLIP; cellular FLICE-inhibitory protein; cyt C; cytochrome C; cytochrome p450 isoform 2B6; cytoglobin; dexamethasone-induced gene 2; dig2; erythropoietin; estrogen response element; glucagon-like peptide-1; glutathione peroxidase-1; glyceraldehyde-3-phosphate dehydrogenase; hypoxia inducible factor-1; hypoxia response element; iron responsive elements; mTOR; mammalian target of rapamycin; metallothionein; miRNAs; microRNAs; oxygen dependent degradation; pVHL; phosphoglycerate kinase-1; prolyl hydroxylases; reactive oxygen species; regulated in development and DNA damage responses 1; renal cell carcinomas; secretion signal peptide; shRNA; short hairpin RNA; siRNA; simian virus 40; small interfering RNA; stimulating protein-1; transactivation domain; two-step transcription amplification; tyrosine hydroxylase; unfolded protein response; untranslated region; vascular endothelial growth factor; von Hippel–Lindau protein.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Gene Expression Regulation*
  • Genetic Therapy / methods*
  • Humans
  • Hypoxia / genetics*
  • Hypoxia / metabolism
  • Hypoxia / therapy*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Promoter Regions, Genetic
  • Untranslated Regions


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Untranslated Regions