Transcriptionally Targeted Adenovirus Vectors

Abstract

Adenovirus vectors are the most highly efficient vehicles currently available for gene transfer to mammalian cells. Their ability to transduce both proliferating and non-dividing cells allows in vivo gene delivery, but the wide spectrum of cell types infected by adenovirus necessitates a requirement for targeting, particularly if the transduced gene is detrimental when expressed in inappropriate tissues. Over the past decade, numerous investigators have examined tissue- or tumor-specific enhancer-promoters as a means to transcriptionally target genes delivered by adenovirus vectors. We review here recent developments in adenovirus vectors including improvements in the vector backbone to maintain promoter specificity. In addition, we discuss the regulatory elements directing cell-specific expression of genes encoding telomerase, prostate-specific antigen, probasin, osteocalcin, tyrosinase, alpha-fetoprotein, surfactant B, and mammaglobin. Recent results using these regulatory sequences to target Ad vectors to cancer cells are highlighted.

Heart-targeted adeno-associated viral vectors selected by in vivo biopanning of a random viral display peptide library

“…In earlier studies, rAAV2-R484E;R585E showed strongly reduced transduction of mouse hepatic tissue in vivo, with slight increase in heart transduction. 26,38 Thus, this experiment should clarify whether the ablation of heparin binding alone-which may result from insertion of a peptide at position R588-would result in similarly increased heart targeting (Figures 3b [4] and [5] and c [4] and [5]). Mutation of the heparin-binding motifs indeed slightly increased heart infection and dramatically reduced liver transduction.…”

“…Mutation of the heparin-binding motifs indeed slightly increased heart infection and dramatically reduced liver transduction. However, a broad distribution in other organs and a significant accumulation in the skeletal [4] and [5] and c [4] and [5]), clearly indicating a positive targeting effect of the two selected peptides.…”

“…So far, cell receptor-directed targeting and expression targeting are the most successfully applied techniques. [1][2][3][4][5][6] Capsids of adeno-associated virus (AAV)-derived vectors have been modified for receptor targeting basically in three ways: (1) by conjugating receptorbinding ligands to their capsids, (2) by genetic insertion of ligands into the capsid (for reviews see Muzyczka and Warrington 1 and Buning et al 7 ) and (3) by DNA shuffling from different AAV serotypes. [8][9][10] Pseudotyping of AAV vectors with capsids of different serotypes also expanded the range of infectable cells, 11 but has not resulted in cell type-selective transduction after systemic application.…”

Tumor suppressor BLU inhibits proliferation of nasopharyngeal carcinoma cells by regulation of cell cycle, c-Jun N-terminal kinase and the cyclin D1 promoter

“…In recent years, human adenovirus (Ad) has been widely used as a vector for gene transfer to mammalian cells, owing to its ability to effectively infect a wide variety of cells [20]. Replication deficient viruses proliferate for weeks in hosts with cancer or other diseases, enabling the restored expression of a defected gene to achieve therapeutic goals.…”

Modifications to the INSM1 promoter to preserve specificity and activity for use in adenoviral gene therapy of neuroendocrine carcinomas

“…Approaches have been made to transcriptionally regulate the expression of therapeutic genes in cancer cells reviewed in references. [2][3][4][5][6][7][8][9][10][11][12] However, interference from the adenoviral sequences can significantly alter the transcriptional control. [13][14][15][16][17] One proven method to block interference of the adenoviral sequences with tissue-specific or -inducible promoters is to include the chicken b-globin HS4 insulator element.…”