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Biotech / Medical : Human Genome Sciences, Inc. (HGSI) -- Ignore unavailable to you. Want to Upgrade?

To: Steven Rachbach who wrote (249)	2/23/1999 1:35:00 AM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 1127

Steven, Thanks for informative post. Still, there seams to be several confusing statements. What is VEGF-1 and what VEGF-2? I thought that human VEGF (as receptor ligand) has only one main form (protein chain of 121 ac), and all others form are different only in protein extension with additional ac (VEGF165, VEGF187, VEGF2XX,..). However, EC express several different VEGF receptors. So which gene-VEGF vector did Dr. Symes used? <<. In that trial, the protein (not the gene) was administered by intravenous line (not into the heart) and patients failed to show an improvement. That's not a surprise to me at all. I think the medication must be injected into the target area directly. I don't think a protein floating around the body has a real chance to "grow" blood vessels in the heart. Further, there is a rational for using the gene rather than the protein. If the gene if injected directly into heart muscle tissue, it can get integrated into the cell and then crank out protein. After some time, the genes degrades and its effects cease. The gene may last longer than the protein it produces and so the gene treatment may be superior to the protein treatment. In conclusion, the encouraging results of injecting the VEGF-1 gene directly into the heart bodes well for HGSI's VEGF-2 and the fact that systemically administered VEGF-1 protein failed to improve cardiac patients was almost a forgone conclusion. >> First, how you know that patients didn't show improvement? Trial didn't reach its primary end point (improvement on treadmill test) at significant level. I agree that i.v route is probably not the best choice for VEGF165 and higher form. But, not because protein float around. It is because of the low bioavailability (165 bind to heparin, albumin, and others transport plasma proteins), and because of this binding it cause hypotension. So, therapeutic dose is simply to low. Contrary to this is pharmacology of the VEGF121. Did you ever consider what may be gene-vector protein delivery side effects and problems? For instance over expression of the VEGF and blood vessel likage! Systemic toxicity (because of the conc. differential in target site compared to rest) will be reduced, but what about local toxicity? Or, who and what will stimulate protein production after gene is inserted? CAD and PVD should be treated by acute not chronic therapy, imo. Probably, there are more concerns and problems about gene therapy which has to be solved in future. Miljenko