Pharmacological interventions for improving adenovirus usage in gene therapy.
Gene therapy may be an innovative and promising new treatment strategy for cancer but is limited due to a low efficiency and specificity of gene delivery to the target cells. Adenovirus is the preferred gene therapy vector for systemic delivery because of its unparalleled in vivo transduction efficiency. Intravenous administration of low doses of adenovirus results in adenovirus sequestration in the liver due to binding to the scavenger receptor present on Kupffer cells. When the amount of adenovirus surpasses the binding capacity of Kupffer cells, hepatocytes absorb adenovirus particles in a blood factor-dependent manner. Increasing the Ad dose even more will saturate both the Kupffer cells and hepatocytes. Then sinusoid endothelial cells bind adenovirus particles in an RGD motif-dependent manner. Strategies to eradicate the binding to liver cells include drugs to interfere or eliminate binding to specific cell types, adenovirus capsid protein mutations and chemical modifications of adenovirus to shield the capsid proteins from cellular receptors. The combined use of these approaches should ultimately lead to successful systemic application of adenovirus in humans.
Haisma
Hidde J
HJ
Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, Groningen University, Groningen, The Netherlands.
Bellu
Anna Rita
AR
D000256:Adenoviridae / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism