SR-A and SREC-I are Kupffer and endothelial cell receptors for helper-dependent adenoviral vectors.
Helper-dependent adenoviral (HDAd) vectors can mediate long-term, high-level transgene expression from transduced hepatocytes with no chronic toxicity. However, a toxic acute response with potentially lethal consequences has hindered their clinical applications. Liver sinusoidal endothelial cells (LSECs) and Kupffer cells are major barriers to efficient hepatocyte transduction. Understanding the mechanisms of adenoviral vector uptake by non-parenchymal cells may allow the development of strategies aimed at overcoming these important barriers and to achieve preferential hepatocyte gene transfer with reduced toxicity. Scavenger receptors on Kupffer cells bind adenoviral particles and remove them from the circulation, thus preventing hepatocyte transduction. In the present study, we show that HDAd particles interact in vitro and in vivo with scavenger receptor-A (SR-A) and with scavenger receptor expressed on endothelial cells-I (SREC-I) and we exploited this knowledge to increase the efficiency of hepatocyte transduction by HDAd vectors in vivo through blocking of SR-A and SREC-I with specific fragments antigen-binding (Fabs).
Telethon Institute of Genetics and Medicine, Naples, Italy.
Pasquale
P
Piccolo
Francesco
F
Vetrini
Pratibha
P
Mithbaokar
Nathan C
NC
Grove
Terry
T
Bertin
Donna
D
Palmer
Philip
P
Ng
Nicola
N
Brunetti-Pierri
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000235:genetics*; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics*; D051117:Scavenger Receptors, Class A / Q000235:genetics*; D051128:Scavenger Receptors, Class F / Q000235:genetics*
D037263:Asialoglycoprotein Receptor; C072264:Kupffer cell receptor; D011971:Receptors, Immunologic; D051117:Scavenger Receptors, Class A; D051128:Scavenger Receptors, Class F