It's unclear to me how they're dealing with this in the trials for arteriovenous grafts for hemodialysis. I gather the graft is ex vivo at some point, and that it's not a synthetic one. Once again, I can find precious little info about the methodology being used in the trial. The PR says:
>>This Phase I/II clinical trial is a double-blind, randomized, placebo- controlled study that will enroll 60 patients at up to 20 leading research centers in the United States. The companies expect to announce initial data from this trial in the first half of 2005.
At the time of graft placement, the patient's recipient vein will receive a single treatment with either E2F Decoy or placebo. The study's endpoint is a fistulogram (i.e., x-ray examination using contrast agent) at six months to observe the amount of blockage in the AV graft. Secondary endpoints include determining safety, as well as efficacy of E2F Decoy treatment versus placebo on graft failure, revision or access graft blood flow.<<
But the scientific founders have been toying with in vivo delivery for various indications . . .
In one recent patent one finds (in Example 3) this:
>>After vascular injury of the common carotid, the distal injured segment was transiently isolated by temporary ligatures. The HVJ complex was infused into the segment and incubated for 10 min at room temperature. No adverse neurological or vascular effects were observed in any animal undergoing this procedure. <<
patft.uspto.gov
Some reference to in situ decoy delivery mentioned here:
jci.org
Which led me here:
>>Hum Gene Ther. 1999 Sep 20;10(14):2355-64.
A pressure-mediated nonviral method for efficient arterial gene and oligonucleotide transfer.
von der Leyen HE, Braun-Dullaeus R, Mann MJ, Zhang L, Niebauer J, Dzau VJ.
Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, CA 94305, USA.
In this study, we report a method of controlled pressure-mediated delivery of "naked" DNA that achieves efficient and safe arterial gene and oligonucleotide transfer. We demonstrated a pressure-dependent uptake of fluorescein-labeled (FITC) oligonucleotide (ODN) in rabbit carotid arteries with preexisting neointimal hyperplasia, using nondistending intravascular delivery pressures ranging from 0 to 760 mm Hg. At an infusion pressure of 50 mm Hg, 10.5+/-5% of neointimal cell nuclei were positive for nuclear uptake of FITC-ODN 4 days after transfection. With an infusion pressure of 760 mm Hg, the transfection efficiency increased to 84.2+/-5.3% of neointimal cells, and to 64.5+/-11.6 and 92.4+/-5.5% of medial and adventitial cells, respectively. Similar patterns of FITC-ODN uptake were seen in atherosclerotic injured arteries. We also investigated the pressure-mediated delivery of plasmid DNA. Transfection of a luciferase expression plasmid, using an infusion pressure of 760 mm Hg, yielded luciferase expression of 816.6+/-108.6 fg/mg protein in normal rabbit carotid arteries, as compared with 38.9+/-23.7 fg/mg protein at 100 mm Hg. Luciferase expression was significantly higher in pressure-transfected injured atherosclerotic arteries (5467.3+/-1047.6 fg/mg protein at 760 mm Hg). Transfection of beta-galactosidase indicated that significant transgene expression occurred in the neointima and media. These data indicate that this pressure-mediated transfection method yields efficient oligonucleotide delivery and enhances transduction with plasmid DNA in normal as well as injured nonatherosclerotic or atherosclerotic arteries.<<
I don't understand the market; are shunts preferable to grafts or fistulae (some patients not suited for one or the other; infection; or?)? In other words, if one solved the problem in grafts, would anybody bother with shunts anymore?
Aside to rkrw: in post 10 I said the Japanese team behind the AHA abstract involving E2F and NFkB was apparently unrelated. Shot from the hip and missed on that one. They've been working with Dzau and Mann for years.
Cheers, Tuck |
