Right-to-lifers denounce it as the drug from hell. Pro-choicers acclaimRU 486 as an elegant, oral alternative to surgical abortion. Now the"abortion pill" has a new assignment.An American cell biologist is exploiting RU 486's anti-progesteronespecialty for an entirely new, and thus far experimental, purpose _ asan on/off switch in gene therapy.So far, RU 486 has been kept off the U.S. market by the fear of itsEuropean manufacturers that an American anti-abortion protest wouldswamp all their non-controversial products.But in May, buoyed by the Clinton administration's pro-choiceposition, the French pharmaceutical giant, Roussel-Uclaf (the "RU" inRU 486) assigned its patent rights to the not-for-profit, New York-based Population Council, which is working to make the drug availableto the America public by 1996.RU 486 terminates pregnancy because it inhibits the hormoneprogesterone, which promotes gestation. It does so by blocking thehormone's receptor.Besides the 200,000 pregnant women in France, Britain andScandinavia who have used the drug as an abortion pill, RU 486 is alsoemployed clinically in Europe to treat several malignancies, mostnotably breast cancer, but also meningioma brain tumors."These have progesterone receptors," said cell biologist Bert O'Malley,of Baylor College of Medicine in Houston, "so if you inhibit them, youinhibit the tumor."O'Malley's patented system consists essentially of harnessing a givengene of interest in the same vector with a second gene, a mutatedsynthetic steroid receptor, engineered to come to life in the presence ofRU 486. Thus, when this expression package is transferred into thetissues of a patient, the therapeutic gene can only be activated by anorally ingested dose of RU 486, or some other anti-progestin. And thehigher the dose, the longer and stronger the expression.O'Malley reported his gene switch demonstration in the Aug. 16 issueof the Proceedings of the National Academy of Sciences (PNAS). Itstitle: "A regulatory system for use in gene transfer.""There's nothing magic about RU 486," O'Malley told BioWorldToday. "We tested six anti-progestins, and they all worked just aswell."But, he explained, "We chose RU 486 because it's been used clinicallynow for a long time on many people in Europe, so its toxicity isknown; it's safe. That enabled us to circumvent some time-consumingand costly new-drug development steps. And people want to startapplying this into humans quickly."A Switch For Parkinson's DiseaseHe used gene therapy for Parkinson's disease (PD) as a working modelin his paper. The target gene was tyrosine hydroxylase, (TH) anenzyme that synthesizes dopamine, the neurotransmitter lacking in thestriatum brain tissue of PD patients. To demonstrate their gene-switchvector, he and his colleagues at Baylor inserted the TH gene along withtheir regulator construct into a rat fibroblast cell line, which dulyexpressed and repressed the gene in response to RU 486 dosage.Because the anti-progestin was blocking a synthetic receptor in a vectorrather than a natural progesterone receptor in a living uterus, thedosage of drug was a minuscule 1,000th of the amount administered inthe abortion-pill version of the compound.O'Malley describes his gene-switch, which is licensed for furtherdevelopment to Houston-based GeneMedecine, Inc., as "a technology-based invention." So, as to its potential therapeutic applications, hesaid, "Our feeling is for companies and clinical situations _ you nameyour gene." He added, "Whatever you want to treat, you put in there,and you can express it when you take RU 486. When you stop takingthe anti-progestin, you'll not produce it any more."For gene therapists focused on neurological diseases, he suggested, "agene that has to do with making more dopa for PD, or oxidation-reduction for Alzheimer's, or some growth factors for nerveregeneration."He continued, "If you're talking about peripheral treatments, say, oneof the new factors that stimulates marrow or blood production, theretoo, you put the gene in, then turn it on or off at will."In current, mostly viral-vectored, gene therapy approaches, O'Malleycautioned, "If you just put the gene in and have it constitutively on, yourun a risk of going past the beneficial phase and overproducing potentmaterial, which could cause deleterious effects."This is strikingly exemplified in transgenic animals, where the gene ismicroinjected into the embryo, he cautioned, "with all the toxicityeffects if it's expressed in earlier experimental stages." His gene switchinjects a dormant DNA sequence into the future transgenic animal,"With the gene switch, you can never have it on till later in life, whenyou give the RU 486 and turn it on."The prospect of such versatile transgenic mammals, O'Malleyobserved, "has attracted quite a bit of commercial interest."GeneMedicine, of which O'Malley is a scientific founder, announcedthis week that it has received a $75,000 Small Business InnovationResearch Grant from the National Institutes of Health to develop drug-controlled gene therapies using its gene-switch technology for in vivopreclinical trials.Besides the neurodegenerative diseases, such as PD and AD, saidGeneMedicine's president and CEO, Eric Tomlinson, the company isaiming to treat immunological and inflammatory diseases and cancers."The gene switch," he said, "could be the enabling factor forcontrolling the pathways of tightly regulated cell growth anddifferentiation, such as those found in the brain and immune system."GeneMedicine's vice president of clinical development, Fred Ledley,cited "The other direction in which this is going, as part of our alliancewith Syntex (USA), Inc. of Palo Alto, is in gene therapy forinflammatory diseases, such as arthritis." He told BioWorld Today thatby replacing the present gene switch with one mimicking aglucocorticoid domain, so "when we treat it with an anti-progestin suchas RU 486, it acts as if its been hit by cortisone, this may be a greatanti-inflammatory molecule."Ledley sees gene therapy under gene-switch control as "something likeregular medicine," instead of a heroic procedure, under day-to-daycontrol by the patient and the physician.But the RU 486 gene switch, he added, "would be contraindicated inpregnancy." n081894RU486

-- David N. Leff Science Editor

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