AAV serotype 8-mediated gene delivery of a soluble VEGF receptor to the CNS for the treatment of glioblastoma.
The presence of the blood-brain barrier complicates drug delivery in the development of therapeutic agents for the treatment of glioblastoma multiforme (GBM). The use of local gene transfer in the brain has the potential to overcome this delivery barrier by allowing the expression of therapeutic agents directly at the tumor site. In this study, we describe the development of a recombinant adeno-associated (rAAV) serotype 8 vector that encodes an optimized soluble inhibitor, termed sVEGFR1/R2, of vascular endothelial growth factor (VEGF). VEGF is an angiogenic factor highly up-regulated in GBM tumor tissue and correlates with disease progression. In subcutaneous models of GBM, VEGF inhibition following rAAV-mediated gene transfer significantly reduces overall tumor volume and increases median survival time following a single administration of vector. Using orthotopic brain tumor models of GBM, we find that direct intracranial administration of the rAAV-sVEGFR1/R2 vector to the tumor site demonstrates anti-tumor efficacy at doses that are not efficacious following systemic delivery of the vector. We propose that rAAV-mediated gene transfer of a potent soluble VEGF inhibitor in the CNS represents an effective antiangiogenic treatment strategy for GBM.
Cell Genesys, Inc., 500 Forbes Boulevard, South San Francisco, CA 94080, USA. thomash@cellgenesys.com
Thomas C
TC
Harding
Alshad S
AS
Lalani
Byron N
BN
Roberts
Satya
S
Yendluri
Bo
B
Luan
Kathryn E
KE
Koprivnikar
Melissa
M
Gonzalez-Edick
Guang
G
Huan-Tu
Randy
R
Musterer
Melinda J
MJ
VanRoey
Tomoko
T
Ozawa
Richard A
RA
LeCouter
Dennis
D
Deen
Peter J
PJ
Dickinson
Karin
K
Jooss
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000378:metabolism*; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D011923:Rats, Nude; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012703:Serotyping; D012995:Solubility; D014183:Transplantation, Heterologous
D040262:Receptors, Vascular Endothelial Growth Factor