STRASBOURG, France _ It was good news and bad news for viralvectors here Wednesday, the first day of the J.P. Lecocq Gene Therapyconference.Enzo Paoletti, founder of Virogenetics Corp., Troy, N.Y., said, duringhis presentation on pox viruses as potential vectors, that a clinical trialof recombinant malaria vaccine was imminent. Unlike other malariavaccines, his comprises genes expressing antigens against all sevenlife-cycle stages of the P. falciparum parasite, five of which passthrough the human liver.Paoletti told BioWorld Today that the human trial already has beenapproved by the FDA, and will start "within a few months," under theauspices of the Walter Reed Hospitals research.The seven genes will be packaged in a vector, NYVAC-Pf7, which heconstructed from a highly attenuated derivative of the Copenhagenstrain of vaccinia virus. This, he told the meeting, "involved the precisedeletion of 18 open reading frames." He added that the vector "is 10million times more favorable than the Wyeth vaccinia virus, whichhelped wipe out smallpox."Also at the conference:y Richard Jude Samulski, University of North Carolina, Chapel Hill,mentioned almost in passing that an adeno-associated virus (AAV) hehas developed as a vector will soon be tried clinically in a patient withFanconi's anemia, a form of cancer. That study already has receivedRecombinant DNA Advisory Committee clearance, and is now pendingFDA approval.Fanconi's anemia is a DNA repair disorder, which turns cells malignantwhen their chromosomes lose stability. AAV, a dependent parvovirus,functions only in coinfection with an adenovirus or certain herpesviruses to produce infection in cultured cells."AAVs," Samulski said, "have advantages as vectors: For example,they are ubiquitous in humans, and are completely non-pathogenic."y A. Dusty Miller, of the Fred Hutchinson Cancer Research Center, inSeattle, told BioWorld Today of a Phase I/II clinical gene therapy trialawaiting FDA approval. It aims to restore the missing gene for thecerebrosidase enzyme to patients with Gaucher's disease. Its vector isbased on the Gibbon Ape Leukemia Virus, for which he has cloned thereceptor.Miller expects that his Gaucher's study "is half a year away."Besides these pending trials, the good news at a more basic sciencelevel, along with the bad, emerged from Wednesday's session:y Jean-Luc Darlix, of the retrovirus lab at INSERM (France's ResearchInstitute for Health and Medicine) in Lyon, reported that he hasdeveloped a retrotransposon vector "two times more efficient and muchshorter" than current retroviral vectors."This," Darlix observed, "leaves more genetic space for gene transfers.These retrotransposons, he added, "not only package gene sequences,but their signal promotes expression of genes downstream."But on the bad news side of the ledger, he mentioned "disappointing"efforts to improve the titer by mutation.y The Salk Institute's Indra Verma also experienced mixed results indeveloping gene therapy for hemophilia. Targeting the gene for FactorIX, his research began by using a retroviral vector to infect mousefibroblasts with the sequence, and found "the monster IX protein in theserum." But the gene expression, so promising in vitro, was notsustained in vivo, in hemophiliac dogs. "There was a transcriptionalshut-off," he reported. "No one knows why."Suspecting mismatched promoters, he switched from fibroblasts tomyoblasts _ noting that they make up to 40 percent of human bodyweight. The gene, for muscle-creating kinase, worked, producingmuscle myotubes, but with much less protein _ anotherdisappointment. Given his in vitro success, Verma is now pursuingexperiments with wild-type dogs and mice in efforts to overcome thestubborn failure of bringing this lab feat to life.y Much debate involved the third early region (E3) of the type 5adenovirus. Is it "non-essential," hence deletable in vectorconstruction? Or does it serve an occult purpose?Columbia University's Harold Ginsberg, who chaired the vectorsession, said of the E3 deletion that nature "would not have saved 10percent of the adenovirus genome to do nothing."He added that its deletion coincides with a marked increase inpathological response to infection. n
-- David N. Leff Science Editor
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