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Inhibitory effects of human sera on adenovirus-mediated gene transfer into rat liver
S Kuriyama1, K Tominaga, M Kikukawa
1Third Department of Internal Medicine, Nara Medical University, Japan.
Abstract:
Recent advances in molecular biology have made gene therapy for cancer feasible in clinical trials. Although recombinant adenovirus is an attractive vehicle for transferring therapeutic genes in vivo, animal studies have indicated that the clinical usefulness of adenovirus vectors may be limited by their immunogenicity. It has been shown that neutralizing antibodies against adenoviruses reduce the efficiency of vector readministration. It is of great importance to examine the effects of human sera on adenovirus-mediated gene transfer, because the majority of prospective gene therapy patients are likely to have been exposed to wild-type adenoviruses. In the present study, it was shown that anti-adenovirus antibody-positive human sera with the lowest positive titer substantially inhibit the adenovirus-mediated gene transfer not only in vitro but also in vivo. These results may have important implications for efficacy considerations when adenovirus vectors are employed in the clinical setting.
Insights
Human antibodies against adenoviruses significantly hinder gene therapy effectiveness, even at low levels. This impacts the clinical use of adenovirus vectors for cancer treatment.
Area of Science:
- Molecular Biology
- Gene Therapy
- Immunology
Background:
- Gene therapy for cancer shows promise due to molecular biology advances.
- Adenovirus vectors are effective for in vivo gene transfer but face limitations due to immunogenicity.
- Pre-existing neutralizing antibodies against adenoviruses can reduce vector efficacy and limit re-administration.
Purpose of the Study:
- To investigate the impact of human sera containing anti-adenovirus antibodies on adenovirus-mediated gene transfer.
- To assess the effect of pre-existing immunity on the efficiency of gene therapy vectors in a clinical context.
Main Methods:
- Testing the inhibitory effects of human sera with varying anti-adenovirus antibody titers on adenovirus-mediated gene transfer.
- Evaluating gene transfer efficiency in vitro and in vivo using human serum samples.
Main Results:
- Human sera with even the lowest positive anti-adenovirus antibody titers substantially inhibited adenovirus-mediated gene transfer.
- Inhibition was observed in both in vitro and in vivo experimental models.
- Pre-existing immunity poses a significant barrier to effective adenovirus vector-based gene therapy.
Conclusions:
- The presence of anti-adenovirus antibodies in human sera can significantly impair gene transfer efficiency.
- Clinical application of adenovirus vectors for gene therapy must consider the impact of pre-existing anti-adenovirus immunity.
- Further strategies are needed to overcome antibody-mediated inhibition for successful adenovirus vector-based therapies.