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Researchers hoping to test a novel nonviral gene therapy system in people next year are unsure of approval prospects, following the recent death of a young man who was treated with an experimental viral vector.1 The man's health deteriorated rapidly a day after he was treated with an adenovirus carrying a therapeutic gene to treat ornithine transcarbamylase (OTC) deficiency. R. Michael Blaese Instead of taking the conventional gene therapy approach of delivering missing genes, the novel approach would use chimeraplasts--oligonucleotides containing both DNA and RNA that theoretically correct point mutations by initiating the cell's DNA mismatch repair machinery2--to treat Crigler-Najjar (C-N) syndrome. Children with C-N lack the complete protein necessary to break down toxic bilirubin in the liver and must spend 12-18 hours a day under a blue light to clear bilirubin. Even with that light therapy, their prospects to live into adulthood without a liver transplant are dim. A team including Cliff Steer, a University of Minnesota gene therapy researcher; R. Michael Blaese, president and chief scientific officer of Kimeragen Inc., a Newtown, Pa.-based company that makes the chimeric oligonucleotides; and D. Holmes-Morton, a Lancaster County, Pa., physician whose many Amish and Mennonite patients include children with C-J3 intends to submit an application to the Food and Drug Administration in January 2000 to treat Lancaster County C-J patients. The fallout from the OTC gene therapy death could work either for or against approval of the chimeraplasty approach, Steer admits. The chimeraplasty method doesn't involve any viral components, which works in its favor. An immune response to those components may have contributed to the earlier gene therapy patient's death, Mark Batshaw, the principal investigator in the now-suspended viral trial, suspects. But chimeraplasty has never been tried before in humans, although Steer has done extensive animal studies.4 "The FDA is going to look upon this as a very novel technology," Steer admits. "Novel technologies are looked at with a great deal of concern." However, Blaese sees the new technology as an advantage of sorts. "This technology is so different from the viral vector approach that we don't anticipate any crossover concerns as a result of the adeno tragedy," Blaese comments. "Of course, we have our own set of issues to deal with as we move forward with the FDA." The FDA suspended two other trials involving systematic delivery of adenovirus to the liver, which the C-J trial also targets, albeit intravenously rather than via artery, following the OTC trial death. Nor has an immune response to the therapeutic protein been eliminated as a cause, although Batshaw doesn't think that immune response to the protein was a factor in the OTC trial death. Still, Steer admits that the issue remains a wild card in the C-N chimeraplasty approach. Finally, all proposed gene therapy trials--viral and nonviral--may be slowed as a result of the death, notes Tom Rando, Stanford University gene therapy researcher, who is also doing preclinical chimeraplasty work. "Certainly scrutiny is going to be heightened," Rando notes. Still, Steer remains optimistic. He has already developed a chimeraplasty model to treat OTC, which he hopes in time will prove safer and more effective than the adenoviral approach. But the death sent a sobering reminder to all gene therapy researchers regardless of their favored delivery vehicle. "We have to keep our guard up at all times for any of these gene therapy programs, be it viral vectors or chimeraplasty," Steer concludes. Paul Smaglik can be reached at psmaglik@the-scientist.com. References 1. P. Smaglik, "Gene therapy death: investigators ponder what went wrong," The Scientist, 12[21]:1, Oct. 25, 1999. 2. B.T. Kren et al., "In vivo site-directed mutagenesis of the factor IX gene by chimeric RNA/DNA oligonucleotides," Nature Medicine, 4:285-90, 1998. 3. S.P. Hoffert, "Taking the clinic to the patients gave researcher sense of purpose," The Scientist, 12[10]:11, May 11, 1998. 4. B.T. Kren et al., "Correction of the UDP-glucuronosyltransferase gene defect in the Gunn rat model of Crigler-Najjar syndrome type I with a chimeric oligonucleotide," Proceedings of the National Academy of Sciences, 96:10349-54, Aug. 31, 1999.

Gene Therapy Death May Delay New Trials

Nov 7, 1999

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