Advances and Future Challenges in Adenoviral Vector Pharmacology and Targeting

Abstract

Adenovirus is a robust vector for therapeutic applications, but its use is limited by our understanding of its complex in vivo pharmacology. In this review we describe the necessity of identifying its natural, widespread, and multifaceted interactions with the host since this information will be crucial for efficiently redirecting virus into target cells. In the rational design of vectors, the notion of overcoming a sequence of viral “sinks” must be combined with re-targeting to target populations with capsid as well as shielding the vectors from pre-existing or toxic immune responses. It must also be noted that most known adenoviral pharmacology is deduced from the most commonly used serotypes, Ad5 and Ad2. However, these serotypes may not represent all adenoviruses, and may not even represent the most useful vectors for all purposes. Chimeras between Ad serotypes may become useful in engineering vectors that can selectively evade substantial viral traps, such as Kupffer cells, while retaining the robust qualities of Ad5. Similarly, vectorizing other Ad serotypes may become useful in avoiding immunity against Ad5 altogether. Taken together, this research on basic adenovirus biology will be necessary in developing vectors that interact more strategically with the host for the most optimal therapeutic effect.

CD46-Mediated Transduction of a Species D Adenovirus Vaccine Improves Mucosal Vaccine Efficacy

“…Species C viruses were also much more capable of infecting macrophages as compared with all of the species D viruses. This observation has been observed in other studies in which Ad was used to eliminate Kupffer cells that ultimately allowed for greater transgene expression Khare et al, 2011). Most interestingly, the species D Ads were much more capable of transducing the professional antigen presenting human dendritic cells.…”

Development of a generic adenovirus delivery system based on structure-guided design of bispecific trimeric DARPin adapters

“…Future studies will elucidate the efficacy of the trimeric adapters in vivo in combination with Ads that are ablated in their interaction of cells mediated by the fiber, penton base, or hexon protein (14).…”

“…For efficient targeting of Ad5, a first major task is to ablate the virion's natural tropism, and this ablation has been achieved by introducing mutations into the knob, hexon, and/or penton base within motifs mediating interactions with cell-surface molecules or blood components, leading to reduced transduction efficiency (13)(14)(15)(16)(17)(18)(19). The second challenge is to retarget the Ad5 specifically to the diseased cells/tissue.…”

“…Previously we and others have reported the use of bispecific adapters binding to a virus capsid protein for specific adenovirus-mediated targeting (14,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). The successful execution of the adapter strategy depends critically on our ability to design protein adapters for Ad that allow the targeting of any desired disease-associated receptor and whose association with the Ad virion is highly stable and can be fine-tuned to be compatible with the virion's structural integrity and its stepwise disintegration during cell entry (38).…”

Gene Delivery Systems: Recent Progress in Viral and Non-Viral Therapy

“…Non-enveloped viruses can be kept in lyophilized form in a stable state inside a flacon tube or capsule; they can be transported without cold chain; by mediating in high transduction effectiveness in dividing and non-dividing cells, they can form 104 virus particles per infected cell (Khare et al, 2011). Adenoviruses achieve suitable transduction through a high level of expression and become beneficial in in vivo conditions (Muzzonigro et al, 1999).…”