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ISIS TEAM DETERMINES THAT ANTISENSE COMPOUNDS MAY BE EFFECTIVE AGAINST CANCER

 CARLSBAD, Calif., July 12 /PRNewswire/ -- A promising new approach for developing antisense drugs against cancer was described in the Journal of Biological Chemistry this week. The paper, "Evaluation of 2'-Modified Oligonucleotides Containing 2'-Deoxy Gaps as Antisense Inhibitors of Gene Expression," published by Brett P. Monia and colleagues of Isis Pharmaceuticals Inc. (NASDAQ: ISIP), describes studies of novel antisense compounds in living cancer cells against the Ha-ras oncogene known to be active in a wide range of human cancers. This week's paper advances the findings published in the same journal in October 1992 by the Isis research team.
 Key findings include:
 -- The use of two different, or chimeric, chemistries in designing an antisense compound resulted in an increased affinity of the compound to bind with its target gene -- Ha-ras.
 -- The Isis team observed activation of cellular mechanisms that degraded Ha-ras.
 -- The critical feature of the new compound is the use of chimeric chemistries in a single antisense molecule.
 -- The second-generation antisense compound is more potent and specific than the first generation molecules described last fall.
 Taken together, the papers demonstrate that a new chemical class of highly potent drugs can be developed which inactivate harmful genes and restore normal growth patterns in cells. Equally important for future drug design is the demonstration that, when carefully controlled studies are performed, increasing affinity of oligonucleotide drugs for their target RNAs results in increased potency or activity.
 What is ras?
 Ras is a normal human gene involved in the regulation of cell growth. Mutations of the ras gene have been found to be active in a large percentage of human tumors. These mutations usually involve a single "point mutation" or coding change in genetic content, yet have profound, and often deleterious, effects on cell behavior.
 First Generation Chemistries
 In the 1992 publication, the Isis team described antisense compounds consisting of phosphorothioate oligonucleotides, which specifically inhibited expression of the cancer-causing mutant ras gene. Importantly, these compounds had very limited effects on the normal ras messenger RNA, and the difference between the normal and mutant products were consistent with the models developed by Isis scientists.
 Second Generation Chemistries
 In today's publication, Monia and his collaborators describe antisense compounds against Ha-ras which take advantage of second- generation oligonucleotide chemistries under development at Isis. The use of these new approaches has enabled Isis to create compounds with enhanced ability in living cancer cells to inactivate mutant ras, and, thus, to restore normal growth patterns to cells.
 The critical feature of the new compounds is the use of two different chemistries in a single antisense molecule. The ends of the compound consist of nucleotide analogs which enhance the binding of the antisense drug to the target messenger RNA for mutant ras. These ends are "RNA-like" in composition. The middle of the antisense molecule has chemistry similar to that of DNA in certain critical aspects. The binding of this "DNA-like" region to its complementary sequence in the target ras messenger RNA stimulates a cellular enzyme, called RNAse-H, to degrade the ras messenger. Furthermore, the antisense compound remains intact because its basic phosphorothioate chemistry protects it from degradation by cellular and other enzymes. The novel oligonucleotides are as much as 15 times as potent as the parent first- generation compounds.
 Portions of this work were undertaken under a research collaboration with Rhone-Poulenc, which is concluding on schedule at the end of July 1993.
 Isis Pharmaceuticals Inc., based in northern San Diego County, is engaged in the discovery and development of a new chemical class of novel oligonucleotide-based human therapeutic compounds. Isis has a broad oligonucleotide research program and multiple compounds in preclinical development. The company's first oligonucleotide-based drug, ISIS 2105, is in pivotal Phase II clinical trials.
 -0- 7/12/93
 /CONTACT: Jacqueline Siegel, Ph.D., VP & CFO of Isis Pharmaceuticals, 619-931-9200/
 (ISIP)


CO: Isis Pharmaceuticals Inc. ST: California IN: MTC SU:

JL-MF -- SD003 -- 0295 07/12/93 09:45 EDT
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Date:Jul 12, 1993
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