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Mar 15, 2011 (Vol. 31, No. 6)

GEN's 30th Anniversary: Antisense

  • Triple Helix

    However, Dr. Peter Dervan, of the California Institute of Technology (Pasadena, CA), has taken the field in a new direction by developing oligonucleotides that bind double-stranded DNA. The technique is known as the triple helix, and it is based on sophisticated organic chemistry. Dr. Dervan and his colleagues have found that a short, synthetic oligonucleotide, 15 to 25 base pairs in length, will bind specifically to a segment of double helix, forming a short triple helix. The oligonucleotide both binds and cleaves DNA, which could prevent normal gene expression.

    “As molecular biology defines specific disease states at the DNA level, a chemotherapeutic strategy of ‘artificial repressors’ based on triple helix forming DNA become a possibility,” says Dr. Dervan.

    The triple helix stratagem is still far from being fully developed, he admits. First, synthetic oligonucleotides are now only available for recognizing guanine and adenine.

    “Assuming we will find oligonucleotides that recognize all four base pairs, we still have to construct them to be nuclease resistant and to be permeable to cell membranes,” says Dr. Dervan. “But I am optimistic that [such DNA analogs] will be created. The anti-sense area is taking off.”

    Indeed, some of the most exciting results have come from research teams at the Worcester Foundation for Experimental Biology, the National Cancer Institute at the National Institutes of Health, and Northwestern University, which have helped to show that anti-sense agents can block the damage of the human immunodeficiency virus.

    Gilead president Michael Riordan says his company is working on the three previously mentioned anti-sense stratagems and told GEN that, “There are others under wraps. We are doing broad-based genetic targeting.”

    The company, he says, “of about 16 staff,” was organized “about a year ago” with $2 million in funding from Menlo Ventures in Menlo Park, CA, a company for which Riordan worked earlier. Equipped with a Hopkins M.D., and a Harvard MBA, Riordan, 31, has spent most of his professional life not in the clinics or at the lab bench, but at business meetings. But, by the accounts of both colleagues and competitors, he has succeeded in recruiting top chemists to his company. Their efforts are key to determining the commercial future of anti-sense agents.

    An early goal of the company is to develop nucleic acid analogs that bind mRNA, and block gene translation. At the same time, work must be done to advance automated synthesis to reduce the costs of making anti-sense compounds.

    A subsequent goal is to develop agents that act directly on the target gene, such as an oncogene, protooncogene, or a gene that expresses proteins that trigger autoimmune disease.

  • Rejected Paper

    Dr. James Summerton, president of Antivirals, the other privately held company dedicated to anti-sense agents, claims to have been working on the anti-sense concept since 1969, and to have started bench work in his home basement, while working with Oregon State University scientists. “A paper I submitted in 1973 to the Journal of Experimental Biology on anti-sense technique was rejected,” says Dr. Summerton, adding that a rewritten version was published in 1979.

    His company is developing two techniques, neu-genes (for neutral genes), which bind to single-stranded genetic sequences. Antivirals was founded in 1980 and, for the last four years, has been financed at an average rate of $200,000 annually through federal grants, equity investments and support from Du Pont (which dropped out in May 1987). Antivirals is in advanced negotiations with Glaxo and Mitsui for further funding. The State of Oregon is also assisting.

    Dr. Summerton says that his anti-sense agents are superior to those of others because, “We have a more radical design of oligonucleotides that allows for the use of inexpensive technology. We can use cheaper reagents and we can build (the oligonucleotides) more easily.”

    In particular, they have built anti-sense agents whose component subunits are derived from the ribonucleosides, rather than the more expensive deoxyribonucleosides. “The major starting materials for our agents would run about three percent of the cost of starting materials for competing agents,” says Dr. Summerton.

    Moreover, he adds that anti-sense agents built from these starting materials have the virtues of easily penetrating tissues and of being insensitive to destructive nucleases; that is, they are tough and can be targeted.

    Dr. Summerton admits that, “for the desired commercial success we will require a prompt financial investment in our program, estimated on the order of $14 million over four years, plus a close collaboration with a major partner…”

    Clearly, both Gilead and Antivirals are trying to accelerate their development program in the face of newly gained “bandwagon status” for anti-sense research.

    What Dr. Summerton does not want is, “a commercial situation, much like that today in the field of recombinant DNA, where multiple companies are all trying to commercialize the same products…”

    Dr. Riordan is not sure that dilemma can be avoided. “All indications are that the field is too elegant and direct to be ignored,” he says.

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