Current Advances and Future Challenges in Adenoviral Vector Biology and Targeting

Abstract

Gene delivery vectors based on Adenoviral (Ad) vectors have enormous potential for the treatment of both hereditary and acquired disease. Detailed structural analysis of the Ad virion, combined with functional studies has broadened our knowledge of the structure/function relationships between Ad vectors and host cells/tissues and substantial achievement has been made towards a thorough understanding of the biology of Ad vectors. The widespread use of Ad vectors for clinical gene therapy is compromised by their inherent immunogenicity. The generation of safer and more effective Ad vectors, targeted to the site of disease, has therefore become a great ambition in the field of Ad vector development. This review provides a synopsis of the structure/function relationships between Ad vectors and host systems and summarizes the many innovative approaches towards achieving Ad vector targeting.

HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice

“…25 The use of bispecific molecules that act as bridges between virions and target cells [67][68][69][70] has been limited because of the instability of the virion-ligand complex in vivo. This can be avoided by genetic approaches that incorporate targeting peptides into viral capsid components, including the fiber, hexon and pIX proteins.…”

“…Two common strategies for altering viral tropism have been genetic modification of the viral fiber gene and/or use of bispecific molecules that act as a bridge between the virus and a target cell surface protein. 24,25 Ad5 fiber is a homotrimeric protein of 186 kDa that protrudes from each of the 12 vertices of the viral particle. The protein is composed of a 44-amino-acid (aa) N-terminal tail that anchors fiber to the penton base through non-covalent interactions, a 355 aa b-spiral shaft extending away from the capsid and a 181 aa globular knob domain at the extreme C terminus that is essential for trimerization.…”

Gene Delivery Systems: Tailoring Vectors to Reach Specific Tissues

“…Seven polypeptides form this complex capsid: hexon (II), penton base (III), fiber (IV), IIIa, VI, VIII, and IX (Campos & Barry, 2007;Sharma et al, 2009). The cell receptor depends on the virus subgroup: A, E and F subgroups use the cell surface coxsackievirus B and adenovirus receptor (CAR); B1 and B2 subgroups use CD46, CD80/86, receptor X, or heparan sulfate proteoglycan (HSPG); C subgroup uses CAR, HSPG, MHC-I, vascular cell adhesion molecule-I (VCAM-I), or integrins; and D subgroup uses CAR, sialic acid, or CD46 (Arnberg, 2009;Campos & Barry, 2007;Sharma et al, 2009). Adenoviral vectors have been used as tools for gene therapy since the late 80s (Friedmann, 1992), and the first clinical trial was started in 1993 (Douglas, 2007).…”

“…In this section we will explore different strategies for AdV retargeting that include genetic modification of the capsid, use of molecular adaptors and chemical modification of the capsid ( Fig. 2) (Campos & Barry, 2007).…”

Characterization of Pulmonary T Cell Response to Helper-Dependent Adenoviral Vectors following Intranasal Delivery

“…T he ability of adenoviral-derived vectors to transduce a wide variety of cells, both dividing and nondividing, has led to their development as an efficient system for pulmonary gene transfer (1). However, the problems of host adaptive and innate immune responses have limited the use of adenoviral vectors for gene therapy, because of concern for their safety and efficacy in vivo.…”