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.