VANCOUVER, B.C. _ One of Wednesday's speakers at the XIInternational Conference On AIDS, Didier Trono, associate professorat The Salk Institute for Biological Studies, said molecular biologyresearch studies have had a profound impact not only on ourunderstanding of AIDS pathogenesis but also on novel approachesfor the development and monitoring of antiviral therapies.
However, Trono, of La Jolla, Calif., suggested that currentlyavailable antiviral drugs have a rather narrow focus, targeting onlytwo of the many reactions key to HIV replication _ namely, thecopying of viral RNA into DNA by reverse transcriptase, and thecleavages mediated by protease during virion maturation.
With current knowledge there are many more therapeutic targetsavailable for investigation.
"Given the fact that HIV has 14 unique proteins, our efforts to dissectthe molecular mechanisms of viral replication should thereforeintensify," he said, "so that not only two, but a number of criticalfunctions will in the future become the targets of antiretroviraltherapy."
New technologies on the horizon that promise to fulfill Trono'sappeal include the rapidly emerging field of gene therapy. A numberof biotechnology companies already are involved in developing noveltherapeutics using antisense approaches and the early results fromsome of these companies were presented at the conference.
Enzo Biochem Inc., of Farmingdale, N.Y., have developed a DNAconstruct, that, when introduced into immune cells become resistantto multiple challenges of HIV-1. The construct, designatedpNDU1A,B,C, has been designed to produce three different antisensesequences, each directed against specific HIV-1 target sequenceswithin two functional regions, tar and tat/rev.
According to findings released at the conference by Norman Kelker,senior vice president of Enzo, the introduction of the antisense RNA-producing DNA construct confers CD4+ monocytic cells with a highlevel of resistance to HIV-1 challenges. In fact, the cells survivedthree successive challenges and functioned normally whereas controlcells, without the construct, were completely destroyed by the virus inthe first challenge.
"We now have successfully demonstrated that we can create CD4+cells that are resistant to HIV-1," Kelker said. "Our antisense therapyalone, or in combination with already established protocols, canbecome an effective and widely applied treatment for HIV-infectedindividuals."
The company now intends to start developing protocols for humanclinical studies that involve ex vivo therapy. Immune cells removedfrom the patient would have the antisense producing genesintroduced. The altered cells would then be reimplanted where theywould be expected to propagate HIV-resistant cells.
Results from Hybridon Inc.'s (of Worcester, Mass.) GEM91antisense compound were presented by Harvard University scientistRandal Byrn. In vitro tests have demonstrated that GEM91 hassignificant inhibitory effects on HIV-1's ability to replicate.
Byrn, assistant professor of Medicine at Harvard Medical School,reported that the results showed that GEM91 appeared to have anumber of mechanisms of action that operate at different stages in theHIV-1 replication cycle.
GEM91 is Hybridon's first clinical compound based on thecompany's proprietary gene expression modulation (GEM) antisensetechnology. Currently in Phase Ib/II clinical trials, GEM91 has beensafely administered to more than 170 subjects at medical centers inthe U.S., France and the U.K. The product is formulated as aninjectable which is being developed to enable ease of use in long-term treatment.
Lea Brakier-Gingras described the results of research that she isconducting at the University of Montreal in association with theMontreal-based biotechnology company Theratechnologies Inc.
The aim of the research is to interfere with a specific step of HIVreplication, the synthesis of the gag-pol protein. This protein is theprecursor of some key enzymatic functions that are required by HIVin order to replicate.
Using a lead compound, designated as TH9407, Brakier-Gingrasreported that the molecule can efficiently interfere with a processcalled ribosomal frameshifting in cultured human fibroblasts.
The results to date show that a two-fold decrease in ribosomalframeshifting was observed in vitro. The compound interfered withHIV-1 proliferation in CD4+ cells transfected with HIV-1 DNA.
Brakier-Gingras said since the target of the potential therapy is thehost ribosomes, which are independent of virus mutability, the risk ofthe emergence of drug-resistant viral strains is extremely unlikely. n
-- Peter Winter Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.