Preclinical data on an antisense compound for inhibiting HIV gene expression were presented Tuesday at the Ninth International Conference on AIDS in Berlin. Sudhir Agrawal, chief scientific officer of Hybridon Inc., reported that the compound, 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 strains of HIV-1. Researchers at the Worcester, Mass., company used an in vitro assay in which they cultured HIV-1-infected cells taken from AIDS patients. "In infected cells isolated from human AIDS patients, GEM 91 has been effective in suppressing the growth of HIV-1 in most known strains, including AZT and ddI resistant strains of the virus," Agrawal said.

Hybridon's GEM 91 antisense compound (as well as the others in its gene expression modulation series) is a synthetic oligodeoxynucleotide (designed to bind to messenger RNA)whose backbone has been chemically modified to form a phosphorothioate derivative. This modification adds stability to the antisense construct and protects it from being degraded. And although only a fraction of the compound actually enters the cells from the surrounding medium, it's concentrated 100 fold (to 25 micromolar) inside the cells, explained Jamal Temsamani, a senior research scientist at Hybridon. Moreover, although there is "more oligo in the (target cell's) cytoplasm than in the nucleus, that's what we want. The translation machinery, the main site of action of antisense compounds, is in the cytoplasm," Temsamani told BioWorld.

Hybridon filed an investigational new drug (IND) application on GEM 91 for inhibiting HIV replication in November 1992. The company is currently wrapping up a series of safety and dosing studies in several quarantined monkeys to answer questions from the FDA's anti-viral center. If all goes well, the company plans to initially enroll some 20 asymptomatic or mildly asymptomatic AIDS patients with CD4 cell counts between 200 and 500, in Phase I safety and dosage trials in the U.S. That trial will be sponsored by the AIDS Clinical Trial Group of the National Institute of Allergy and Infectious Diseases.

-- Jennifer Van Brunt Senior Editor

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