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Published on: October 26, 2018
Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus)
R Alba1, A C Bradshaw, N Mestre-Francés
1Division of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
Abstract:
Coagulation factor X (FX)-binding ablated adenovirus type 5 (Ad5) vectors have been genetically engineered to ablate the interaction with FX, resulting in substantially reduced hepatocyte transduction following intravenous administration in rodents. Here, we quantify viral genomes and gene transfer mediated by Ad5 and FX-binding-ablated Ad5 vectors in non-human primates. Ad5 vectors accumulated in and mediated gene transfer predominantly to the liver, whereas FX-binding-ablated vectors primarily targeted the spleen but showed negligible liver gene transfer. In addition, we show that Ad5 binding to hepatocytes may be due to the presence of heparan sulfate proteoglycans (HSPGs) on the cell membrane. Therefore, the Ad5-FX-HSPG pathway mediating liver gene transfer in rodents is also the mechanism underlying Ad5 hepatocyte transduction in Microcebus murinus.
Insights
Genetically engineered adenovirus type 5 (Ad5) vectors lacking coagulation factor X (FX) binding showed reduced liver gene transfer in non-human primates, primarily targeting the spleen instead. This highlights the Ad5-FX-heparan sulfate proteoglycan (HSPG) pathway
Area of Science:
- * Viral vector gene therapy
- * Hepatocyte transduction
- * Non-human primate models
Background:
- * Adenovirus type 5 (Ad5) vectors are utilized for gene therapy but exhibit significant liver tropism.
- * Previous studies in rodents indicated that ablating coagulation factor X (FX) binding reduces Ad5 liver transduction.
- * The role of FX and heparan sulfate proteoglycans (HSPGs) in Ad5 liver tropism requires further investigation in relevant preclinical models.
Purpose of the Study:
- * To evaluate the biodistribution and gene transfer efficiency of wild-type Ad5 and FX-binding-ablated Ad5 vectors in non-human primates.
- * To investigate the role of the FX-binding pathway in Ad5-mediated liver transduction in a primate model.
- * To confirm the involvement of HSPGs in Ad5 hepatocyte binding and transduction.
Main Methods:
- * Intravenous administration of Ad5 and FX-binding-ablated Ad5 vectors in non-human primates.
- * Quantification of viral genomes in various organs, with a focus on liver and spleen.
- * Assessment of gene transfer efficiency mediated by the vectors.
- * In vitro studies to investigate Ad5 binding to hepatocytes and the role of HSPGs.
Main Results:
- * Wild-type Ad5 vectors predominantly accumulated in the liver, mediating significant gene transfer.
- * FX-binding-ablated Ad5 vectors showed a distinct tropism, primarily targeting the spleen with negligible liver transduction.
- * Ad5 binding to hepatocytes was found to be mediated by heparan sulfate proteoglycans (HSPGs).
Conclusions:
- * The FX-binding pathway is crucial for Ad5-mediated liver gene transfer in non-human primates, similar to rodent models.
- * Targeting the spleen represents a potential alternative for Ad5 vector delivery by ablating FX binding.
- * The Ad5-FX-HSPG pathway is conserved and underlies Ad5 hepatocyte transduction in Microcebus murinus, validating its relevance for gene therapy strategies.
