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1.
Virology ; 561: 87-97, 2021 09.
Article in English | MEDLINE | ID: mdl-34171766

ABSTRACT

Efficacy of oncolytic, conditionally-replicating adenovirus (CRAd) vectors can be enhanced by "arming" the vector with therapeutic transgenes. We examined whether inclusion of an intact early region 3 (E3) and the reptilian reovirus fusogenic p14 fusion-associated small transmembrane (FAST) protein enhanced vector efficacy. The p14 FAST transgene was cloned between the fiber gene and E4 region, with an upstream splice acceptor for replication-dependent expression from the major late promoter. In A549 cells, this vector expressed p14 FAST protein at very low levels, and showed a poor ability to mediate cell-cell fusion, relative to a similar vector encoding p14 FAST within the E3 deletion. Although expression of E3 proteins from the CRAd increased plaque size, poor expression of p14 FAST protein compromised the fusogenic capacity of the vector. Thus, location of a therapeutic transgene within a CRAd can significantly impact expression of the transgene and is an important consideration in vector design.


Subject(s)
Adenovirus E3 Proteins/genetics , Adenoviruses, Human/genetics , Genetic Vectors , Oncolytic Viruses/genetics , Transgenes , Viral Fusion Proteins/genetics , A549 Cells , Adenovirus E3 Proteins/metabolism , Adenoviruses, Human/physiology , Gene Expression , Genome, Viral , HEK293 Cells , Humans , Oncolytic Viruses/physiology , RNA Splicing , Viral Fusion Proteins/metabolism
2.
Cancer Gene Ther ; 28(7-8): 745-756, 2021 08.
Article in English | MEDLINE | ID: mdl-32606392

ABSTRACT

Oncolytic viruses are designed to replicate in and kill cancer cells, and have shown tremendous promise in preclinical and clinical studies. Indeed, several oncolytic viruses are available to patients in a number of different countries around the world. However, most oncolytic viruses show a poor ability to spread throughout the tumor mass, frequently leading to only a partial response and regrowth of the tumor. One approach to improve spread of the viral effect throughout the tumor mass is to arm the oncolytic virus with a fusogenic protein. In this manner, a single infected cell can fuse with many adjacent uninfected cells, essentially amplifying the anti-tumor effects. In this review, we discuss the development and use of fusogenic proteins to enhance the efficacy of human adenovirus-based vectors for cancer therapy.


Subject(s)
Adenoviridae/drug effects , Cell Fusion/methods , Neoplasms/drug therapy , Oncolytic Virotherapy/methods , Humans
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