Dr Juliana Small of the University of Pennsylvania, Drs Raj Kurupati, Xianqyang Zhou and their colleagues from the Wistar Institute have developed a novel adenoviral vector for delivery of multiple transgenes.
Gene therapy using an adenovirus vector: a new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell; if the treatment is successful, the new gene will make a functional protein. Image credit: U.S. National Library of Medicine.
With the genetic basis of a number of human diseases known, many attempts have been made to treat the disorders by adding back the correct genetic information to individual cells. Adding foreign genetic material to treat disorders comes under the realm of gene therapy.
Conceptualized in 1972, gene therapy trials to treat human disorders began in 1990s. These initial trials did a disservice to this exciting and promising field, as they were conducted too prematurely as highlighted by initial dramatic clinical failures.
The field, however, has survived, and now bolstered by a second wind is poised to make a lasting impact on human health.
For gene therapy to work, the correct genetic information has to be packaged and delivered to target cells.
Adenoviral packaging vectors are attractive options for human gene therapy trials since they show low pathogenicity, high viral yields, carry large genes, and show transgene specific B and T cell responses. When packaged with recognizable antigens from various diseases, these vectors may serve as vaccines.
Novel vaccines targeting complex pathogens like HIV, HCV, TB, malaria, influenza as well as cancer is a long-standing goal of human gene therapy.
A team jointly led by Dr Small, Dr Kurupati, and Dr Zhou in the laboratory of Prof Hildegund Ertl at the Wistar Institute has designed a novel adenoviral expression system by inserting two separate expression cassettes into two separate loci (E1 & E3) in an adenoviral vector of chimpanzee origin.
This is a marked improvement from earlier adenoviral vectors that have issues concerning their safety, stability, and large-scale production.
Moreover, the future of gene therapy delivery system is expected to support multiple transgene expression from the same vector; this study is a critical step in the right direction.
In their recent work, published in the journal Human Gene Therapy, the scientists show the use of chimpanzee adenoviral vaccine system that was chosen to circumvent the broad pre-existing neutralizing antibodies; a problem usually encountered when using human adenoviral vectors.
Moreover, the serendipitous synergism from two expression cassettes increased the gene expression and protein product, while maintaining genetic stability.
In vivo results in mice following immunization with these vectors improved antibody production and enhanced CD8 T cell response.
Overall, this work demonstrates that the dual expression adenoviral vectors could potentially be used for gene therapy targeting multivalent pathogen, multiple pathogens or cancer.
Bhuminder Singh, Ph.D.
(Bhuminder Singh is a research fellow at Vanderbilt University. A cancer researcher by profession, he loves to read about science, its history and evolution as new techniques and ideas integrate with or replace old ones. Twitter: @bhumi_singh).
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Small JC et al. 2014. Construction and characterization of E1- and E3-deleted adenovirus vectors expressing two antigens from two separate expression cassettes. Hum Gene Ther. 25 (4): 328-38; doi: 10.1089/hum.2013.216
