Telomerase-Dependent Gene Therapy

Thomas      Wirth; Florian      Kuhnel; Stefan      Kubicka

Abstract

Adenovirus-mediated gene therapy approaches have evolved as promising means for cancer treatment during the last decade. Utilizing a broad spectrum of tumor-specific promoters, numerous oncotropic vectors have been created with exceptional properties regarding tumor-restricted specificity. The discovery of telomerase, its high prevalence in tumor tissues and the discovery of its transcriptional regulation via the hTERT promoter have extended the applicability of adenoviral gene therapy vectors to approximately 90% of all tumors. First generation adenoviral vectors expressing transgenes under the control of the hTERT promoter confirmed the therapeutic potential but were restricted to initially transduced cancer cells. Recently, telomerase-dependent conditionally replicative adenoviral vectors (CRADs) have been developed that combine the specificity of hTERT promoter based expression systems with the lytic efficacy of replicative viruses. To evaluate the potential for clinical applications, various efforts have been made to establish combinative strategies including systemic chemotherapy, radiotherapy and antiangiogenesis. This review highlights the rapid advances of telomerase-based gene therapy and gives insight into future prospects and future development of oncotropic vectors.

Keywords: cancer, transgene expression, cell transduction, viral vectors, conditionally replicative adenoviruses (crads), telomere elongation (alt), expression, htert promoter, estrogen