Four out of five gene therapy trials approved in the U.S. rely onretroviruses to carry their gene of therapeutic interest into a targetcell's genome. Most of these viral vectors use attenuated mouseleukemia viruses _ which have their shortcomings."They can infect only a limited range of target cells," notesmolecular biologist Maribeth Eiden, who heads the molecularvirology unit at the National Institute of Mental Health (NIMH)."As gibbon ape leukemia virus was obviously isolated from aprimate," she told BioWorld Today, "it can efficiently infect a largenumber of human cells, including many lymphocytes and bloodcells, which up to now were not efficiently infected by murineleukemia viruses." She added, "Of course, the target cell of mosthuman gene therapy protocols is the human stem cell, and that isnot efficiently infected by existing vectors."Gibbon ape leukemia virus (GaLV) has a broader host range thanthe murine model, according to NIMH's pending patent. Anannouncement submitted last week to the Federal Register by theNational Institutes of Health's Office of Technology Transfer(OTT) invites "pharmaceutical or biotechnology companies" toapply for an exclusive or non-exclusive Cooperative Research andDevelopment Agreement (CRADA), and/or patent licensures, tocommercialize "The Use of Novel Retroviral Vectors With GibbonApe Leukemia Virus (GaLV) Components."How Gibbon Bests Mouse"GaLV uses a cell surface internalization receptor that is differentfrom those of the available retroviral vectors, and thus allowsinfection of cells and tissues normally resistant to retroviralinfection," reads Eiden's patent application."We have demonstrated that this group of primate retroviruses canassemble with murine leukemia virus components," Eiden said,"which opens up a whole new avenue of retroviral vector design,for gene therapy and making transgenic animals." She continued,"It should provide the gene therapist with a repertoire of vectorsthat would greatly improve the efficiency of retroviral gene therapyin human patients."Her gibbon-derived vectors, Eiden suggests, aims to complementexisting murine cloning vehicles, rather than replace them.The NIMH lab's latest cloning vehicle, she said, "consists of agibbon ape viral genome and a mouse core. "In many cases," shesaid, "it supersedes, or has improved delivery in vitro, to specificcell types, when compared to its murine counterpart."Eiden allows that "Despite the higher degree of success we haveachieved in infecting cells with the GaLV compared to the murineLV, I can't predict that our genome will be any more successfulthan methods of therapeutic gene delivery that have beendisappointing to date."Ultimate Goal Calls For Partner(s)Her laboratory has constructed a full-length genomic plasmid cloneof GaLV that can replicate efficiently in a broad range of targetcells, following calcium-phosphate mediated gene transfer. On thistemplate it has installed GaLV-based packageable genomesencoding bacterial b-galactosidase and neomycinphosphotransferase.Eiden's long-range goal, with the help of one or more industrialpartners, is to create all-primate vectors, composed of GaLVgenome, core and envelope."The reason I'm looking for an industrial partner in this endeavor,"she said, "is simply that I don't work with animals, I don't workwith patients. My limitations are that I can make it in vitro but Ican't test it ex vivo. So it would be nice to get somebody who eitherworks more closely with animals, or is interested in therapeuticgene applications."She added, "We're making the second generation of genomes thathas the poly-linker in it, which would make it more accessible toprospective partners. Then that would finalize those collaborations.""A good many companies," Eiden said, have beaten a path to herdoor at NIMH, and one in particular has said "a definite `yes'" to aCRADA. "This is now pending in the Office of TechnologyTransfer," she explained, "which has just filed its notice in theFederal Register."Editor's Note: For licensing proposals, consult OTT contractspecialist Carol Lavrich, (301) 496-7735, ext. 287; for CRADAinformation, Kathleen Conn, NIMH, (301) 496-8826.; for technicalquestions concerning these vectors, Maribeth Eiden, (301) 496-0483. n
-- David N. Leff Science Editor
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