Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia.
Numerous clinical trials are utilizing mesenchymal stem cells (MSC) to treat critical limb ischemia, primarily for their ability to secrete signals that promote revascularization. These cells have demonstrated clinical safety, but their efficacy has been limited, possibly because these paracrine signals are secreted at subtherapeutic levels. In these studies the combination of cell and gene therapy was evaluated by engineering MSC with a lentivirus to overexpress vascular endothelial growth factor (VEGF). To achieve clinical compliance, the number of viral insertions was limited to 1-2 copies/cell and a constitutive promoter with demonstrated clinical safety was used. MSC/VEGF showed statistically significant increases in blood flow restoration as compared with sham controls, and more consistent improvements as compared with nontransduced MSC. Safety of MSC/VEGF was assessed in terms of genomic stability, rule-out tumorigenicity, and absence of edema or hemangiomas in vivo. In terms of retention, injected MSC/VEGF showed a steady decline over time, with a very small fraction of MSC/VEGF remaining for up to 4.5 months. Additional safety studies completed include absence of replication competent lentivirus, sterility tests, and absence of VSV-G viral envelope coding plasmid. These preclinical studies are directed toward a planned phase 1 clinical trial to treat critical limb ischemia.
Institute for Regenerative Cures, University of California Davis , Sacramento, California, USA.
Julie R
JR
Beegle
Institute for Regenerative Cures, University of California Davis , Sacramento, California, USA.
Nataly Lessa
NL
Magner
Institute for Regenerative Cures, University of California Davis , Sacramento, California, USA.
Stefanos
S
Kalomoiris
Institute for Regenerative Cures, University of California Davis , Sacramento, California, USA.
Aja
A
Harding
Institute for Regenerative Cures, University of California Davis , Sacramento, California, USA.
Ping
P
Zhou
Institute for Regenerative Cures, University of California Davis , Sacramento, California, USA.
Catherine
C
Nacey
Institute for Regenerative Cures, University of California Davis , Sacramento, California, USA.
Jeannine Logan
JL
White
Institute for Regenerative Cures, University of California Davis , Sacramento, California, USA.
Karen
K
Pepper
Institute for Regenerative Cures, University of California Davis , Sacramento, California, USA.
William
W
Gruenloh
Institute for Regenerative Cures, University of California Davis , Sacramento, California, USA.
Geralyn
G
Annett
Institute for Regenerative Cures, University of California Davis, Sacramento, California, USA; Department of Cell Biology and Human Anatomy, University of California Davis, Sacramento, California, USA.
Jan A
JA
Nolta
Institute for Regenerative Cures, University of California Davis, Sacramento, California, USA; Department of Cell Biology and Human Anatomy, University of California Davis, Sacramento, California, USA.
Fernando A
FA
Fierro