MEDICAL MAGIC New gene techniques could revolutionize the drug industry

When M. James Barrett knocked on the doors of big drug companies in 1987, he was peddling dreams.

He had no magic cure in a vial, no recipe for a drug, just a good hunch that a technique called gene therapy could revolutionize the way diseases are treated.


"We got a polite reception, but we were not taken seriously," said Dr. Barrett, the 49-year-old biochemist and chief executive of Genetic Therapy Inc. of Gaithersburg.

Today, Genetic Therapy is among a dozen or so companies across the nation poised to turn the stuff of science fiction into reality. In five years, gene therapy and another gee-whiz technology called antisense have gone from fantasy to experimental treatments aimed at big targets: cancer, AIDS, heart disease, cystic fibrosis, sickle cell anemia and other life-threatening diseases.


"We are looking at something that will fundamentally change the pharmaceutical industry," said James W. Hawkins, a molecular biologist and chief executive of Synthecell Corp., a Rockville antisense company.

Instead of searching through thousands of compounds for a new drug, scientists could use advances in genetic engineering to custom-design a cure or treatment for a disease. Theoretically, a defective gene that causes a particular disease could be pinpointed and "fixed" with gene therapy by putting cells with "good" genes into the sick person's body. Or the instructions a defective gene is sending the body could be blocked with antisense.

Treatments based on antisense could be developed in a fraction of the time and at a fraction of the cost traditional drugs require. And, although gene therapy may not turn out to be cheap, it could cure diseases now treatable only at great cost.

Proponents say these therapies will expand or take over drug markets worth billions of dollars.

Already, Genetic Therapy has worked with pioneers in the field at the National Institutes of Health to treat two girls with adenosine deaminase deficiency, a usually fatal condition that forces children to live in sterile bubbles or seclusion in their homes because their immune systems are deficient. The children have improved to the point that they are attending school, surviving chicken pox and leading more normal lives.

Dr. Barrett is betting that the first gene therapy products will be on the commercial market in 1995. And Dr. Hawkins' company already has begun selling synthetic molecules for research and diagnostic purposes.

A person's genes contain the hereditary information that determines whether he or she has green eyes, a good singing voice or susceptibility to a particular disease.

The children with adenosine deaminase deficiency, for instance, have a faulty gene that makes their bodies incapable of combating even the common cold.


With gene therapy, a person with a faulty gene would receive cells containing a good gene. These genes would direct the body to produce either a protein that is lacking or a protein to fight a disease. A cancer patient might be given a gene to boost the body's immune system so that it destroys the malignancy.

Antisense technology, also known as code blocking, combines biotechnology's genetic engineering with traditional chemistry. Companies would make a synthetic chemical that could shut off the disease-causing messages the gene sends to the body. The chemical is designed to block the cell's genetic material -- DNA or RNA -- from making a protein that causes a disease.

The beauty of the process is that it provides a road map for making the antisense product: Scientists examine the structure of the culprit DNA or RNA strand and then make a mirror-image strand that blocks the messages it sends by chemically binding to it. That approach could cut costs by as much 45 percent, Dr. Hawkins said.

Traditional drugs, in contrast, can require searching through thousands of plants or chemical compounds before the right one is found. Some have compared the process to trying a key on thousands of cars until it unlocks one. Even after a promising natural or synthetic compound is found, it can take years to prove its safety and effectiveness.

The average cost of developing a traditional drug is $231 million, according to the Pharmaceutical Manufacturers Association.

Still, genetic therapy and antisense face major hurdles.


With antisense, there are the complicated problems of how to get the new treatment into the body and of determining its effects.

Paul Miller, a professor of biochemistry and leader in antisense research at the Johns Hopkins University working in collaboration with researchers at the University of Maryland Medical School, has shown that antisense inhibits the herpes virus in cell cultures.

"What isn't known," he said, "is how these molecules behave when they are injected" in humans. Much work remains before antisense is proved safe and effective, said Dr. Miller, co-founder of Genta Inc., an antisense company in San Diego.

It will take years of clinical testing before products based on antisense hit the market, but the push to develop them has begun. Genta and Isis Pharmaceutical Inc. in Carlsbad, Calif., recently asked the Food and Drug Administration for permission to begin preliminary testing.

Research on gene therapy is further advanced. However, a critical question remains about whether companies will be able to continue patenting genes for commercial use, thereby keeping competitors away from their niche in the market.

The question goes to the heart of the viability of the business. Companies say that without patent protection they have no incentive to develop products. That view is backed by the federal National Institutes of Health, which has filed for patents for more than 2,000 gene fragments.


NIH officials say they want to encourage commercial markets by licensing rights to genes to companies that would bioengineer medical treatments. Other scientists believe in the time-honored sharing of the fruits of research, including genes.

Until the issue is resolved by the U.S. Patent and Trademark Office, companies such as Genetic Therapy will continue signing agreements with other companies for the commercial use of genes it needs to pair with its gene transportation system.

Genetic Therapy already has its transportation system. The company strips a virus -- nature's most efficient vehicle for getting into a cell -- of the element that makes people sick and uses it to carry a bioengineered gene into a cell in the body.

Although these modified viruses, called vectors, are valuable to the company (it sells these "empty" viruses to researchers), it needs to acquire the exclusive use of genes to insert in the virus to be able to market a therapy.

Advances are eagerly awaited, but no company has profited from gene therapy or antisense, and some people question whether any will.

"There are a lot of unanswered questions," said David Webber, a biotechnology analyst at Alex. Brown & Sons. Most important, "will these things work? All the signs are positive, but we won't know for a while."


Other analysts are as skeptical as the drug companies were when Dr. Barrett approached them in the 1980s. There are too many loose ends, they say, including questions about profitability and the impact on major drug companies' franchises.

"How do you give it to a patient? Does it come in a pill? How do you make a profit on this to underwrite the research and development costs?" said Paul Nadler, Sandoz Pharmaceutical Co. vice president of scientific planning and evaluation. Those were the questions companies asked, he said, sometimes because the concepts are difficult to imagine.

But he is a convert. So is Sandoz, which has invested $100 million in gene therapy, with the purchase of a 60 percent share in Systemix Inc. of Palo Alto, Cal. and an investment in Genetic Therapy.

Despite all the possible drawbacks, other major companies seem interested. Although they won't say so publicly, several are doing research, said Mr. Nadler, who predicts two to five major deals between small start-up companies and big drug companies within 18 months.

Other analysts think the drug companies would have gained nothing from getting into the race earlier. "Why invest a lot of research money if you have a pick of companies out there?" said Richard Purcell, project manager of life sciences at Klein and Co., a New Jersey-based business consulting firm. "They can pick the right horse at the end of the race."

Some industry fortune tellers argue, however, that it will cost the major drug companies a lot more to get into the market today, now that the technologies appear to be viable. Small companies will become more choosy about forming alliances, and the little guys may hold the golden key -- patents -- on much of the new technology.


Gene therapy companies

Genetic Therapy Inc., Gaithersburg; raised $60 million in capital; founded 1986; develops therapies to treat ADA deficiency, cancer, AIDS, cardiovascular disease

Targeted Genetics Corp., Seattle; subsidiary of Immunex since 1989; expects to spin off as independent company; develops treatments for viral infections, cancers, HIV infection.

Somatix Therapy, Alameda, Calif.; raised $70 million in capital; founded 1988; develops gene therapy for cancer, hemophilia, Parkinson's disease.

Transkaryotic Therapies, Cambridge, Mass.; raised $21 million in capital; founded 1988; uses chemical and physical methods to introduce genes into cells, is working on chronic anemia, insulin for diabetics, hypercholesterol and hemophilia.

Viagene Inc. San Diego; raised $18 million in capital plus $40 million lined up over next four years; founded 1987; uses gene transfer technology to stimulate killer T-cells for treating cancers and severe viral infections.


Cell Genesys, Foster City, Calif.; raised $15 million in capital; founded 1989; makes gene targeting and cell transplant products, therapeutic protein products

TargeTech Inc, Meriden, Conn.; raised $2 million in capital; founded 1990; developing gene therapy and antisense drugs that can be injected to treat heart disease, hemophilia and hepatitis.

Antisense companies

Gilead Sciences Inc, Foster City, Calif.; raised $126 million in capital; founded 1987; public, developing code blockers

Genta Inc., San Diego; raised $52 million in capital, founded 1988; public, working on code blockers for leukemia, cancers, inflammatory and infectious diseases.

Isis Pharmaceuticals Inc. Carlsbad, Calif.; raised $78 million in capital; founded in 1989; developing antisense technology to treat genital warts, herpes, cancer, inflammatory disease, infectious diseases.


Synthecell Corp., Rockville; founded 1987; makes synthetic DNA for research and use in living cells.

Triplex Pharmaceutical, Houston; founded 1989; private, public offering planned, developing anti-viral cures.

* TargeTech Inc., see above.