"The balloon angioplasty was a success, but the patient restenosed."This dismal bottom line on a frequent cardiovascular maneuver to openclogged coronary arteries means that all too often the blood vesselsrestenose _ narrow again. Half a million Americans undergo balloonangioplasty yearly, and about 40 percent suffer reblockage. Restenosisalso often follows replacement of sclerotic blood vessels by coronarybypass surgery.To stretch the internal diameter of arteries straitened by atheroscleroticplaque, surgeons thread a slender flexible catheter to the site of theocclusion, and inflate a skinny balloon. This dilates the stenotic vessel,and restores blood flow.But in the process, the operation wounds the delicate arterial lining.The tissue fights back by stepping up proliferation of the smoothmuscle cells that make up much of the artery's middle concentric layer_ the tunica media.To stop those muscle cells from overreacting to the catheter-causedinsult, cardiovascular clinicians are trying all sorts of drugs and bloodproducts. Their latest recourse is the potential of gene therapy.Among gene transfer's major players are internist Gary Nabel andcardiologist Elizabeth Nabel at the University of Michigan MedicalCenter in Ann Arbor. Their current strategy is to introduce therecombinant herpesvirus gene encoding tyrosine kinase (tk), carried byan adenoviral vector to the site of restenosis. There the tk enzymewould render the dividing smooth muscle cells susceptible to a strongcytotoxic antiviral agent, ganciclovir. This drug in turn would causethose cells to self-destruct.After confirming their hypothesis in vitro, they put it to the test in vivo,using a mammal with a circulatory system that closely resembles thatof Homo sapiens. Their animal model of choice was the commondomestic pig, Sus scrofa.Pig, hog and swine are fighting words, when used as epithets. But as asurrogate for modeling arterial restenosis therapy, Sus scrofa is man'sbest friend. As the Nabels point out, "the arterial bed of swine has asize and structure that is histologically and biochemically similar tohuman coronary arteries, including a developed intima [lining]consisting of elastic tissue, collagen, scattered smooth muscle cells andendothelium."Pigs, they noted, can also develop human-like atherosclerosis, and reactto balloon angioplasty with similar restenosis.This week's Science, out Friday, reports the Nabels' preclinical porcinetrial as "Gene Therapy for Vascular Smooth Muscle Cell ProliferationAfter Arterial Injury."First of all, to verify that the cells would indeed express a transfectedgene, the Michigan team injured their animals' iliofemoral (thigh/groin)artery under anesthesia, and infected that blood vessel at the locallesion site with a reporter gene encoding human placental alkalinephosphatase, which is readily detectable.After this checked out, they damaged the right and left iliofemorals ofother pigs at a site isolated between two inflated balloons, thenintroduced the tk-delivering viral vehicle by catheter. A six-dayganciclovir regimen followed.The gene therapists reported a 50 percent to 90 percent reduction inintimal hyperplasia at the site six weeks post-treatment, "of sufficientmagnitude to potentially affect arterial blood flow."An editorial in the same Science acclaims the Nabels' experiment as"the most significant progress yet on the gene therapy front" ofrestenosis. It quotes leading cardiologists as foreseeing that the strategymight become routine practice in conjunction with angioplasty orbypass intervention.On the side of caution, some suggested that the results in healthyporcine arteries need to be replicated in atherosclerotic animals beforeproceeding to human trials. Also, instead of a local site dammedbetween two balloons, some sort of shunt must be devised to permitunimpeded blood flow during the vector inoculation."Prior to beginning clinical trials for humans," Gary Nabel toldBioWorld Today, "we are interested in additional animal trials. Havingshown that the gene transfer technique is effective in normal pigarteries damaged by balloon catheter," he added, the team intends totest the procedure in porcine arteries "that have grown rigid and narrowby plaque buildup. Such an animal model would more closelyapproximate human atherosclerosis." n
-- David N. Leff Science Editor
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