Toward gene therapy of endometriosis: transductional and transcriptional targeting of adenoviral vectors to endometriosis cells

Abstract

OBJECTIVE To screen a panel of targeted adenoviruses as vectors for endometriosis gene therapy. STUDY DESIGN Endometriotic cells were obtained from subjects with ovarian endometriomas. Liver tissues were taken from donors during hepatic transplantation surgery. Human endometriotic cells and liver tissues were transfected by targeted adenoviruses expressing luciferase reporter gene. Luciferase Activity mediated by each virus was expressed as a percentage of adenovirus serotype 5 activity. Two-tailed Student’s t test was used to compare the adenovirus data. RESULTS In endometriosic cells, the adenovirus-RGD (Ad5-RGD-luc), adenovirus under secretory leukocyte protease inhibitor promoter (Ad-SLPI-luc), and adenovirus under heparanse promoter (Ad-heparanase-luc) showed significantly higher activity as compared to the adenovirus serotype 5 (Ad5-CMV-luc). In liver tissues, adenovirus-survivin (Ad-survivin-luc) and Ad-heparanase-luc had significantly lower activity compared with Ad5-CMV-luc. CONCLUSION Ad-heparanase-luc showed “endometriosis on, liver off” phenotype and is promising vector for endometriosis gene therapy.

Mesenchymal Stem Cells: A Promising Tool for Targeted Gene Therapy of Endometriosis

“…Gene therapy holds an exciting promise for the treatment of numerous disorders; a couple of animal studies and in vitro experiments have indicated its application in endometriosis [5,15,41,42]. Potential targets for gene therapy of endometriosis include genes related to angiogenesis, hormonal balance and inflammatory mediators [43].…”

“…Transductional targeting of adenoviruses involves specific modifications in the adenovirus fibers, which includes attachment of targeting peptides, serotype knob switching or fiber replacements [47]. These modifications in the capsid proteins of adenovirus would help in routing its cell entry through receptors that are specifically expressed on pathological tissues [5]. In the transcriptional targeting approach, the vector may initiate non-specific gene transfer to a large number of cells; however, its transgene expression is restricted specifically to the target tissue [47].…”

Towards Fibroid Gene Therapy: Adenovirus-Mediated Delivery of Herpes Simplex Virus 1 Thymidine Kinase Gene/Ganciclovir Shrinks Uterine Leiomyoma in the Eker Rat Model

“…We and others have also utilized similar methods for Ad detection in both preclinical and clinical trials [16,35] . Our attempts to modify the liver tropism of wild-type adenovirus and divert it to the target organ of choice are yielding encouraging results [50,79] .…”

“…Gene therapy success for a genetic disease -severe combined immunodeficiency disease -has been achieved [86,96] , and ongoing gene therapy development includes choosing the appropriate gene, method of gene delivery, achieving temporary or stable transfection, regulating gene expression, avoiding side effects and achieving better results than conventional therapy [47,50,71,78,79,86] .…”

Gene therapy of benign gynecological diseases

“…Transcriptional targeting depends on non selective transfer of the gene to different tissues; however, gene expression will be possible only in pathological tissues through driving the gene expression under tissue-specific promoters that are “on” in pathological tissues but “off” in normal tissues [129]. In a recent publication by our group, we screened a number of transductionally targeted and transcriptionally targeted adenoviruses to detect the ones that can achieve highest gene transfer and expression in endometriosis cells and lowest expression in normal tissues and cells [130]. The targeted adenoviruses used in this study are shown in Table 1.…”