WASHINGTON _ For the first time, gene therapy has entered thedomain of the heart.Researchers at St. Elizabeth's Medical Center and the Tufts UniversitySchool of Medicine in Boston have devised a strategy that will enablethem to sow the genes that promote vascular growth in painfullyclogged peripheral blood vessels. If all goes well, the genes, whichproduce a substance known as vascular endothelial growth factor(VEGF), will promote the development of new blood vessels capableof bypassing the blockage.The study, which last week won unanimous approval of the 23-memberRecombinant DNA Advisory Committee, was one of nine proposalsapproved at the quarterly meeting. Others include novel strategies forthe treatment of cystic fibrosis, mild Hunter's Syndrome and cancers ofthe head, neck and breast. But, of all the proposed trials, it was theBoston study that generated the most excitement among the RACreviewers."This application of gene therapy is completely novel and has greatpromise," said Arno Motulsky, professor of medicine and genetics atthe University of Washington in Seattle."For the first time, we're saying it's safer to infuse DNA than arecombinant protein," said Robert Erickson, professor of pediatrics andmolecular and cellular biology at the University of Arizona, Tucson.The procedure, developed by cardiologist Jeffrey Isner, molecularbiologist Kenneth Walsh and surgeon James Symes, has been likenedto a bypass without the surgeon. The researchers say the technique, ifshown to be safe and effective in this and many subsequent trials, couldprove beneficial for as many as 40,000 Americans each year whodevelop leg artery blockages so severe that the pain never lets up, evenwhen they are at rest. Many develop leg ulcers that cannot heal becausethey are starved of blood dammed up by the blockage.Currently, those patients must have bypass surgery or balloonangioplasty, a procedure which relies on a catheter tipped with aballoon, which is inserted into the occluded artery and then inflated toclear the blockage. Some, whose vessels are beyond repair, mustundergo amputation.Isner and his coworkers have take their cues from the body's ownpotential to respond to blood vessel blockages. The source of thisability is the substances known as angiogenic growth factors, whichwere discovered two decades ago. People who can generate sufficientsupplies of growth factors, can form 10 to 15 collateral blood vesselsthat snake past the blockage and provide a new conduit for blood. Butmany people do not have this capability, which hinges on the ability ofcells lining arteries to produce the growth factors, including VEGF,which signals new arteries to form.The researchers have succeeded in embedding the VEGF genes in apolymer, which can then be used to coat an angioplasty balloon. Theballoon is threaded into the blocked arteries and inflated at the edge ofthe blockage. If the theory holds, the genes will be taken into the cellslining the artery walls. The cells then will begin producing VEGF,which, ideally, will begin to promote blood vessel development.The Phase I trial will involve 12 volunteers, all of whom must have legpain so severe that they have been taking narcotics for a month or legulcers that have persisted for a month despite treatment. The subjectsmust also be unable to undergo bypass surgery or angioplasty, eitherbecause of the location of the occlusion or because they are in poormedical condition.Typically, medicines can do nothing for these sufferers but mask theirpain, Isner and his coworkers said. "There is no evidence to suggestthat any medical therapy is efficacious for patients with rest pain and/orischemic ulcers from [peripheral artery disease]," according to theirRAC proposal. Many sufferers in the U.S. must have lower limbsamputated each year. One in 10 does not survive the surgery. Andeven those who survive the amputation face an uncertain future. Fortypercent die within two years of the operation, Isner and his coworkerssaid. Only 50 percent of those with below-knee and 25 percent of thosewith above-knee amputations ever achieve full mobility.Trials in rabbits have shown that the new strategy may prove useful intreating these patients. The researchers used the rabbits as their owncontrols, meaning that the scientists cut off blood flow in one limb butnot the other. Then researchers infused the VEGF-coated angioplastyballoons. Tests subsequently revealed the presence of human VEGF inthe rabbits' tissues, and by one month, the rabbits had "significantlyhigher" blood vessel density in the treated leg, compared with thecontrol leg.Whether this effect is biological significant _ and reroutes enoughblood to bypass a blockage and ease pain _ remains to be seen. Isnerwarned that the risks include putting a catheter in the few remainingopen blood vessels of someone with a severe blockage. The tip coulddislodge plaque and send it coursing into the heart or brain. Or theprocedure could so badly damage an artery that the patient may have tohave an amputation anyway.Despite the uncertainty and the massive amount of research thatremains to be done before the procedure can be attempted more widely,however, the researchers are optimistic about its prospects. Isner toldone interviewer that the technique may ultimately enable doctors tosimply reroute blood even past blockages that threaten the heart.Among the other protocols approved at the meeting were:_ A study proposed by Terence Flotte, of Johns Hopkins Children'sCenter, Baltimore, for treating adult cystic fibrosis. The researchersplan to load an adeno-associated virus with normal copies of the cysticfibrosis transmembrane conductance regulator (CFTR) gene and use abronchoscope to infuse the combination into a lobe of each subjects'lungs.The researchers have chosen a retrovirus in an effort to achieve stableintegration of the CFTR gene into target cells, an accomplishment thathas eluded researchers using other vectors. Although the RACmembers approved the protocol, they stipulated that precautions mustbe taken to minimize the risk that infection could lead to shedding ofthe viral gene product.Among other precautions, family members of the subjects may betested for exposure to the virus and study drop-outs may be confined inthe hospital for a brief period, until researchers can prove they are nolonger shedding the virus._ A similar trial proposed by Ronald Crystal, of New York Hospital-Cornell Medical Center in Manhattan, would splice the normal CFTRgene into an adenovirus treated so that it is unable to replicate._ A study by Stephen Eck and his coworkers at the University ofPennsylvania Medical Center, Philadelphia, which intended to makebrain tumor cells susceptible to the relatively non-toxic druggancyclovir. All of the subjects will have terminal glioblastomas andastrocytomas. The researchers will inject the drug susceptibility geneHerpes virus thymidine kinase directly into brain tissue, and then treatpatients with gancyclovir. If the theory holds, the gene will convertgancyclovir into a toxic form that can kill tumor cells. n

-- Steve Sternberg Special To BioWorld Today

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