Treatment of osteoarthritis using a helper-dependent adenoviral vector retargeted to chondrocytes.
Osteoarthritis (OA) is a joint disease characterized by degeneration of the articular cartilage, subchondral bone remodeling, and secondary inflammation. It is among the top three causes of chronic disability, and currently there are no treatment options to prevent disease progression. The localized nature of OA makes it an ideal candidate for gene and cell therapy. However, gene and cell therapy of OA is impeded by inefficient gene transduction of chondrocytes. In this study, we developed a broadly applicable system that retargets cell surface receptors by conjugating antibodies to the capsid of helper-dependent adenoviral vectors (HDVs). Specifically, we applied this system to retarget chondrocytes by conjugating an HDV to an α-10 integrin monoclonal antibody (a10mab). We show that a10mab-conjugated HDV (a10mabHDV)-infected chondrocytes efficiently in vitro and in vivo while detargeting other cell types. The therapeutic index of an intra-articular injection of 10mabHDV-expressing proteoglycan 4 (PRG4) into a murine model of post-traumatic OA was 10-fold higher than with standard HDV. Moreover, we show that PRG4 overexpression from articular, superficial zone chondrocytes is effective for chondroprotection in postinjury OA and that α-10 integrin is an effective protein for chondrocyte targeting.
Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas, USA.
Merry Zc
MZ
Ruan
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Laboratory of Immunovirotherapy, Division of Pharmaceutical Biosciences and Center for Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Vincenzo
V
Cerullo
Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas, USA.
Racel
R
Cela
Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas, USA.
Chris
C
Clarke
Xintela AB , Lund, Sweden.
Evy
E
Lundgren-Akerlund
Mayo Clinic, Division of Infectious Disease, Department of Medicine , Rochester, Minnesota, USA.
Michael A
MA
Barry
Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas, USA.
Brendan Hl
BH
Lee