title: GENIS: gene expression of sodium iodide symporter for noninvasive imaging of gene therapy vectors and quantification of gene expression in vivo.
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/mutTK(SR39)rep-hNIS) coexpressing a therapeutic yeast cytosine deaminase (yCD)/mutant herpes simplex virus thymidine kinase (mutTK(SR39)) fusion gene and the hNIS gene was developed. Ad5-yCD/mutTK(SR39)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 Na(99m)TcO(4) using gamma camera scintigraphy. Despite the close proximity of the urinary bladder, (99m)TcO(4)(-) uptake was readily detected in the prostate using viral dose levels (10(10) to 10(12) 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 (99m)TcO(4)(-) 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/I symporter) technology in the clinic will facilitate optimization of future human gene therapy trials.
authors.affiliation: Department of Radiation Oncology, Detroit, Michigan 48202, USA.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Barton
authors.forename: Donald
authors.initials: D
authors.lastname: Tyson
authors.forename: Hans
authors.initials: H
authors.lastname: Stricker
authors.forename: Young S
authors.initials: YS
authors.lastname: Lew
authors.forename: Gregory
authors.initials: G
authors.lastname: Heisey
authors.forename: Sweaty
authors.initials: S
authors.lastname: Koul
authors.forename: Alberto
authors.initials: A
authors.lastname: de la Zerda
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Yin
authors.forename: Hui
authors.initials: H
authors.lastname: Yan
authors.forename: Tavarekere N
authors.initials: TN
authors.lastname: Nagaraja
authors.forename: Kelly Ann
authors.initials: KA
authors.lastname: Randall
authors.forename: Guk Kim
authors.initials: GK
authors.lastname: Jin
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Fenstermacher
authors.forename: Sissy
authors.initials: S
authors.lastname: Jhiang
authors.forename: Jae
authors.initials: J
authors.lastname: Ho Kim
authors.forename: Svend O
authors.initials: SO
authors.lastname: Freytag
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Brown
mesh_terms: D000256:Adenoviridae; D000818:Animals; D003952:Diagnostic Imaging; D004285:Dogs; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D011467:Prostate / Q000473:pathology; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D017556:Technetium Compounds / Q000378:metabolism; D000099209:Sodium-Iodide Symporters
chemical_list: D027981:Symporters; D017556:Technetium Compounds; D000099209:Sodium-Iodide Symporters