APRIL 2003

Gene strategy targets angiogenic blood vessels

By: Karen Sandrick

CONTEXT: A nonviral gene therapy strategy selectively targets angiogenic endothelium for apoptosis, and in the process it destroys the blood supply that supports malignancies. (Science 2002 June 28; 296[5577]:2404-2407). The approach uses the vascular endothelial cell growth factor avß3, which is expressed on the surface of angiogenic blood vessels but not on normal vasculature.

RESULTS: An antiangiogenic gene-targeting tumor vasculature produces pronounced tumor regression in mice. When avß3 was coupled with Raf-1 kinase, a gene that blocks neovascularization, and a positively charged tracking nanoparticle in a mouse study of melanoma, the complex caused massive endothelial apoptosis in 24 hours and significant tumor death surrounding each dying blood vessel in 72 hours.

IMAGE: Mice with implanted melanoma tumors received intravenous injections of avß3/NP-Raf. After 24 hours, the tumors were harvested and stained with VE-cadherin to reveal the presence of endothelial cells, FLAG for gene expression, and TUNEL for apoptosis. Arrowheads (lower right) identify ring of cells undergoing apoptosis. (Reprinted with permission from Science, 28 June 2002:296. Copyright 2002 American Association for the Advancement of Science)

IMPLICATIONS: The avß3 and Raf-1 kinase combination is such a potent inducer of apoptosis in angiogenic blood vessels that principal investigator Dr. John D. Hood and colleagues at The Scripps Research Institute in La Jolla, CA, hope to broaden the vascular targets of gene therapy. They believe the angiogenic one-two punch may be useful for remodeling tissue after myocardial infarction or stroke, suppressing neovascularization due to diabetic retinopathy or macular degeneration, and interfering with angiogenesis in the arthritic joint.