GENIS: Gene expression of sodium iodide symporter for noninvasive imaging of gene therapy vectors and quantification of gene expression in vivo

Kenneth N. Barton, Donald Tyson, Hans Stricker, Young S. Lew, Gregory Heisey, Sweaty Koul, Alberto de la Zerda, Fang Fang Yin, Hui Yan, Tavarekere N. Nagaraja, Kelly Ann Randall, Guk Kim Jin, Joseph D. Fenstermacher, Sissy Jhiang, Jae Ho Kim, Svend O. Freytag, Stephen L. Brown

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

With the goal of optimizing adenovirus-mediated suicide gene therapy for prostate cancer, we have developed a method based on the human sodium iodide symporter (hNIS) that allows for noninvasive monitoring of adenoviral vectors and quantification of gene expression magnitude and volume within the prostate. A replication-competent adenovirus (Ad5-yCD/mutTKSR39 rep-hNIS) coexpressing a therapeutic yeast cytosine deaminase (yCD)/mutant herpes simplex virus thymidine kinase (mutTKSR39) fusion gene and the hNIS gene was developed. Ad5-yCD/ mutTKSR39 rep-hNIS and a replication-defective hNIS adenovirus (rAd-CMV-FLhNIS) were injected into contralateral lobes of the dog prostate and hNIS activity was monitored in live animals following administration of Na99mTcO4 using gamma camera scintigraphy. Despite the close proximity of the urinary bladder, 99mTcO4- uptake was readily detected in the prostate using viral dose levels (1010 to 1012 viral particles) that have been safely administered to humans. Due to its rapid clearance and short physical half-life (6 h), it was possible to obtain daily measurements of 99mTcO4- uptake in vivo, allowing for dynamic monitoring of reporter gene expression within the prostate as well as biodistribution throughout the body. High-resolution autoradiography of prostate sections coupled with 3D reconstruction of gene expression demonstrated that the magnitude and volume of gene expression could be quantified with submillimeter resolution. Implementation of the GENIS (gene expression of Na/l symporter) technology in the clinic will facilitate optimization of future human gene therapy trials.

Original languageEnglish (US)
Pages (from-to)508-518
Number of pages11
JournalMolecular Therapy
Volume8
Issue number3
DOIs
StatePublished - Sep 1 2003

Keywords

  • Adenovirus
  • Nuclear medicine
  • Reporter gene
  • Sodium iodide symporter
  • Suicide gene therapy

ASJC Scopus subject areas

  • Molecular Biology

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