Advances of Recombinant Adenoviral Vectors in Preclinical and Clinical Applications

Abstract

Adenoviruses (Ad) have the potential to induce severe infections in vulnerable patient groups. Therefore, understanding Ad biology and antiviral processes is important to comprehend the signaling cascades during an infection and to initiate appropriate diagnostic and therapeutic interventions. In addition, Ad vector-based vaccines have revealed significant potential in generating robust immune protection and recombinant Ad vectors facilitate efficient gene transfer to treat genetic diseases and are used as oncolytic viruses to treat cancer. Continuous improvements in gene delivery capacity, coupled with advancements in production methods, have enabled widespread application in cancer therapy, vaccine development, and gene therapy on a large scale. This review provides a comprehensive overview of the virus biology, and several aspects of recombinant Ad vectors, as well as the development of Ad vector, are discussed. Moreover, we focus on those Ads that were used in preclinical and clinical applications including regenerative medicine, vaccine development, genome engineering, treatment of genetic diseases, and virotherapy in tumor treatment.

Keywords: adenovirus; adenovirus biology; cancer therapy; gene therapy; oncolytic; vaccine; viral vector.

Figure 1

The life cycle of adenovirus. (1) Adenovirus (Ad) infection begins with the binding of Ad fiber to cellular receptors (e.g., CAR and CD46 or Desmoglein-2). (2) This binding activates the internalization of Ad through endocytosis. (3) During cytoplasmic transport, Ad presents proteins, which, in association with vesicular acidification, allow the release of the virion (4) near the nucleus. (5) The interaction with the nuclear pore complex facilitates the transport of the viral genome into the nucleus. In addition, the replication of Ad is divided into two stages: the early phase (6), during which genes are expressed that code for transcription factors. These factors regulate the expression of other viral genes as well as host cell genes, enabling the completion of the Ad life cycle. Subsequently, viral DNA replication (8) starts along with the expression of proteins encoded by late genes (9). This coordinated activity allows the assembly of new viral particles (10) and new viral particles are released through cell lysis (11). A detailed signaling cascade through virus entry is not presented in detail to preserve the overview. This figure was adapted from [89].

Figure 2

Versatile clinical applications of adenoviral vectors in vaccine design, oncolytic and gene therapy. Adenovirus-mediated gene delivery can be used for vaccine development (as Ad can deliver genes coding for immunogenic proteins into the host, which trigger the development of immunity in the host) and for oncolytic therapy (targeted therapy, which consists of administering recombinant Ads, leading to tumor cell-specific replication of recombinant Ad only in tumor cells and their consequent lysis) [131,132,133].