Recombinant Adenovirus Vector Design for Invading Immune System
The viral vector is a potent gene delivery platform for the treatment of genetic and acquired diseases. The removal of pathogenicity and replication of adenovirus, combined with its ability to carry the therapeutic transgene and to effectively infect numerous mammalian cells makes it amenable for clinical use in gene therapy. Especially, recombinant adenoviral vectors have been extensively used in gene transfer systems. As a leading expert in adenovirus manufacturing, Creative Biolabs offers custom adenovirus services ranging from vector design, small-scale packaging, to large-scale GMP production for animal studies and clinical applications. Our professional team will work with global scientists to accomplish varieties of challenging adenovirus construction programs that best meet clients' needs.
Immune Responses to Viral Vectors
The adenoviral vector is an optimal vehicle for gene delivery due to its capacity to efficiently infect host cells, however, the immune system has evolved to fight off what it detects as invading pathogens. While innate immunity is mostly driven by virion components present on initial administration of the adenovirus into living animals, adaptive immune responses are primarily associated with the leaky expression of adenovirus-derived genes in the early generation of adenoviral vectors, or more importantly driven if the transgene expressed by adenoviral vectors is perceived as immunologically foreign. Thus, innate immunity and antigen-specific adaptive immune response against vector-derived immunogens reduce the stability and efficacy of in vivo gene transfer.
Recombinant Adenovirus Vector Design at Creative Biolabs
Immune responses against adenovirus may target capsid proteins, DNA or RNA genome, viral proteins expressed from vector backbone or incorporated genes, and strictly limit gene therapy in vivo. Systemic delivery of adenoviral vectors leads to rapid physiological reactions, including innate immunity activation, cytokine induction, inflammation, liver toxicity, and thrombocytopenia. Adenoviral vectors with additional deletions in their genome in the adenovirus genes (E2A, E2B, and E4) have been generated. These advanced vectors can produce fewer adenovirus-derived gene products and minimize the induction of vector-specific adaptive immunity. At Creative Biolabs, we're skilled at making newer adenoviral vectors eliciting lower immunogenicity and longer transgene expression, and our services can invade the immune system as below.
- Innate immune responses to adenoviral vectors
- Adaptive immune responses against adenoviral vectors
- Overcoming immune responses in adenoviral gene transfer
Recombinant adenovirus can infect a wide range of cell types with the highest efficiency and this infection isn't dependent on cell division of hosts. It has become a versatile and powerful tool for gene delivery and expression in mammalian cells. Here, we're able to produce custom recombinant adenovirus comprising full-length cDNA, allowing high gene expression, or an adenovirus construct containing RNAi oligos specific to a target gene to perform efficient elimination. In addition, we would also like to provide two kinds of vectors, the shuttle vector containing the gene of interest (GOI) and the recombinant adenovirus vector (pAD), for recombinant adenovirus packaging.
Figure 2. Overview of immune responses to viral vectors. (Nayak, 2010)
Features
- Relative ease of construction
- Infecting both dividing and non-dividing cells
- High virus titers and high levels of expression (observed within 24h)
- Infecting host cells with nearly 100% efficiency
Replication-deficient adenovirus-based recombinant vectors have been the focus of considerable interest in the current for their potential applications in gene therapy and as vaccine vehicles for treating infectious diseases (e.g. human immunodeficiency virus diseases). The innate immune response against adenoviruses is the most significant barrier in clinical practice of adenoviral vectors for gene therapy. At Creative Biolabs, we're always absorbed in exploring and investigating the mechanisms that adenoviral vectors interact with and activate the innate and adaptive immune systems. In this respect, our safer vectors allow for pre-emptive and specific modulation of immune responses in efforts to consider better utilization of these excellent gene transfer platforms. For more information, please feel free to contact us.
Reference
- Nayak, S.; et al. (2010). Progress and prospects: immune responses to viral vectors. Gene Ther. 17(3): 295-304.
