Gene Therapy with Helper-Dependent Adenoviral Vectors: Current Advances and Future Perspectives

Abstract

Recombinant Adenoviral vectors represent one of the best gene transfer platforms due to their ability to efficiently transduce a wide range of quiescent and proliferating cell types from various tissues and species. The activation of an adaptive immune response against the transduced cells is one of the major drawbacks of first generation Adenovirus vectors and has been overcome by the latest generation of recombinant Adenovirus, the Helper-Dependent Adenoviral (HDAd) vectors. HDAds have innovative features including the complete absence of viral coding sequences and the ability to mediate high level transgene expression with negligible chronic toxicity. This review summarizes the many aspects of HDAd biology and structure with a major focus on in vivo gene therapy application and with an emphasis on the unsolved issues that these vectors still presents toward clinical application.

Potential of gene therapy as a treatment for heart failure

“…The E1-E4 proteins elicit a significant innate immune response, which is the major therapeutic challenge in using adenoviruses in human applications. Third-generation "gutless" adenoviral vectors with deleted E1-E4 proteins have a lower immunogenicity profile and partially overcome this obstacle (5). In the heart, adenoviral transgene expression is robust but transient (6).…”

Switching a Replication-Defective Adenoviral Vector into a Replication-Competent, Oncolytic Adenovirus

“…The site-specific recombination has also been used to eliminate helper vector contamination for packaging of helper-dependent (HD) gutless adenoviruses that are devoid of all viral coding sequences (34,35). Immune and inflammatory responses to HD Ads are greatly reduced, allowing for enhanced transgene expression in target tissues (36,37). In comparison, here, we employ a similar engineering strategy to achieve the opposite result: we use an RD vector and RD helper to generate an RC virus utilizing the Flp-mediated recombinatorial approach (21).…”

Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus

“…HDAd are constructed by removing viral sequences from the adenoviral vector genome, except for the packaging sequence. HDAd eliminate the problem of viral gene expression in transfected cells, which accompanies AAV [45]. HDAd have been reported to show long-term expression of transgenes in the pancreas [46].…”