Preclinical data on an antisense compound for inhibiting HIVgene expression were presented Tuesday at the NinthInternational Conference on AIDS in Berlin. Sudhir Agrawal,chief scientific officer of Hybridon Inc., reported that thecompound, GEM91, was able to inhibit the expression of HIV-1-associated proteins by targeting the virus' gag gene sequence,which is believed to be highly invariant in most known strainsof HIV-1. Researchers at the Worcester, Mass., company usedan in vitro assay in which they cultured HIV-1-infected cellstaken from AIDS patients. "In infected cells isolated fromhuman AIDS patients, GEM 91 has been effective insuppressing the growth of HIV-1 in most known strains,including AZT and ddI resistant strains of the virus," Agrawalsaid.
Hybridon's GEM 91 antisense compound (as well as the othersin its gene expression modulation series) is a syntheticoligodeoxynucleotide (designed to bind to messengerRNA)whose backbone has been chemically modified to form aphosphorothioate derivative. This modification adds stability tothe antisense construct and protects it from being degraded.And although only a fraction of the compound actually entersthe cells from the surrounding medium, it's concentrated 100fold (to 25 micromolar) inside the cells, explained JamalTemsamani, a senior research scientist at Hybridon. Moreover,although there is "more oligo in the (target cell's) cytoplasmthan in the nucleus, that's what we want. The translationmachinery, the main site of action of antisense compounds, is inthe cytoplasm," Temsamani told BioWorld.
Hybridon filed an investigational new drug (IND) application onGEM 91 for inhibiting HIV replication in November 1992. Thecompany is currently wrapping up a series of safety and dosingstudies in several quarantined monkeys to answer questionsfrom the FDA's anti-viral center. If all goes well, the companyplans to initially enroll some 20 asymptomatic or mildlyasymptomatic AIDS patients with CD4 cell counts between 200and 500, in Phase I safety and dosage trials in the U.S. Thattrial will be sponsored by the AIDS Clinical Trial Group of theNational Institute of Allergy and Infectious Diseases.
-- Jennifer Van Brunt Senior Editor
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