STRASBOURG, FRANCE _ A press conference last week for sciencejournalists covering the First J.-P. Lecocq Gene Therapy Conferencehere produced exchanges, of which the following truncated samplescapture some of the meeting's scientific substance and flavor:A. Dusty Miller, Fred Hutchinson Cancer Research Center, Seattle:The issue is: Why don't we treat patients who have bone marrowdefects with gene therapy now? The problem is that the rate of genetransfer of bone-marrow stem cells is so low now. Think of monkeys,where hits amount to 0.1 to 1.0 percent genes transferred. And that ratewon't work for thalassemia; it won't work for a lot of these diseases.So until we solve basic problems of improving the transfer rate ofdifferent vectors, or understanding the basic biology of stem cells, wereally can't treat those diseases.Take hemophilia. It goes back to the fact that right now there's noanimal model that shows the level of factor IX that you need over thelong term to really justify a trial.You get good results with adenovirus vectors in compromised animals,but that's not applicable to humans right now.Inder Verma, Salk Institute, La Jolla, Calif.:I should point out that Dusty was in my lab. He started the adenoviruswork.Jean-Michel Bader at Science et Vie magazine; Lancetcorrespondent:How much money did you spend?Miller:In my lab, we got a grant on the order of $100,000 a year. Thatsupported the cloning of a lot of receptors, which gives us insight intoadditional aspects of the science, to help us maybe resolve the problem.It's not fair to say we spent all of that on directed research. Bigcompanies are vested with that aspect, but with basic research younever know where the answers will come from.Betty Dodet, French freelance life sciences reporter based in Lyon:Do you think that you should try other types of viruses that haven'tbeen explored yet, such as adeno-associated virus, very recentlydeveloped as vectors for gene therapy?Miller:Sure! In my lab we have a number of retroviruses that are not related tothe ones we've used, that we're exploring now. Any virus is apossibility, and there are people working on others elsewhere.Verma:Yes, take the poxvirus. It's a very big virus, but has advantages. Whenit comes to novel viral vectors, I say, "Let a hundred flowers bloom!"Bader:What is the bad news exactly about the deletion of the E3 early domainregion in the adenovirus vector?Harold Ginsberg, Columbia University, New York:RAC [the Recombinant-DNA Advisory Committee to NIH] is stillpermitting people in companies and universities to do some clinicaltrial protocols using the AV vector. One of the factors that has to belooked at is that there haven't been very good studies yet in terms ofhow the virus has to be used to get enough gene expression.For example in cystic fibrosis, you may be able to use the amount ofvirus to get down below enough inflammatory response, [the "badnews"], and that's what people are hoping.We may be able to find the precise gene that's doing all this damage. Itstill hasn't been discovered. We know what the damages are, and whatgenes are preventing damage, but what we don't know is what genesare making the production, for example, of [inflammatory] cytokines.Or what are all the viral proteins that are attracting the cytotoxic T cellresponse.Bader:Dr. Ginsberg, suppose your neighbor had a girl who had cystic fibrosis,and she is supposed to be included in one of those RAC protocols _before we get this information. What would you say to her?Ginsberg:If it were a good friend, I'd say "no" to it. Not under the presentcircumstances. Adenovirus is a dangerous vector to put into a personwho's already had pulmonary inflammatory disease.Michael Courtney, Senior Vice-President and Scientific Director,Transgne, Strasbourg:The information is there; we know there is an inflammatory response.Yet RAC has approved these trials, and FDA has approved these trialsof the adenovirus vector, so they should go ahead. Starting at a lowdose, then raising the dose by stages, each approved by FDA.It's not bad news; it's part of a long process.Verma:I hope it will sound a cautionary note to the scientists also. There is anexcitement that makes them feel they have to do something fast. It'sexciting; a lot of pressure. I think the Cystic Fibrosis Foundationexerted enormous pressure to get on with these gene therapy trials.Ginsberg:I think more research should be done before going into human trials. Ithink it's an excellent idea to start with very low doses. I don't thinkthe vector should contain the E3 deletion.Miller:We've had that come up at the RAC meeting. I always ask the peoplewho bring up the question: "Would you rather take those adenoviralgenes on the bus, or would you rather get CFTR, the cystic fibrosisgene, which we all have?"Bader:What about the environment? We know that there has been concernthat trials in the field with recombinant plants that carry genes againstherbicides would give those genes to other plants in nature. Is there anydanger with those adenoviruses that _ we know _ are going to goeverywhere, to the lung, everywhere? That those modifiedadenoviruses, carrying deleterious genes, could recombine with naturaladenoviruses, and then spread?Ginsberg:That has been looked at fairly extensively in cells, and nothing everoccurred to be worried about._ David N. Leff
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