The Cutting Edge: COMPUTING / TECHNOLOGY / INNOVATION : Plying a Murky Gene-Therapy Pool : Biotechnology: A promising field is hindered by red tape, money problems and greed.
When scientists first identified the gene that causes cystic fibrosis back in 1989, those suffering from the disease suddenly had hope. Medical researchers believed it would soon be possible to replace the gene that causes the disease--the most common fatal genetic disorder affecting Caucasians--by using the new tools of biotechnology.
But more than five years later, there is no such treatment for cystic fibrosis: Efforts to develop one have been stalled by a daunting series of technical, regulatory and financial problems. The difficulties encountered in this pioneering effort provide a sobering illustration of the challenges inherent in gene therapy--and accentuate what many believe is a need for greater competition among competing biotech firms and scientists in a hugely promising but unproven field.
“We’re getting so tied up with proprietary interests that this new technology is being heavily stymied,” says Dr. Michael Blaese, chief of the Clinical Gene Therapy Branch of the National Center for Human Genome Research (NCHGR) in Bethesda, Md. “This new field is crying out for leadership. Without that, there will be a very adverse effect on the development of a technology we all think is crucial to 21st-Century medicine.”
Ironically, Blaese and his fellow researcher, Steven Rosenberg, are the co-inventors named on a surprisingly broad gene therapy patent issued Tuesday to Genetic Therapy Inc. of Gaithersburg, Md.
It’s easy to see why so many researchers are excited about the potential of gene therapy. Ever since the basic structure of genes was discovered more than three decades ago, scientists have been gaining more and more understanding of the relationship between complex genetic structures and human characteristics.
The $3-billion government-funded Human Genome Project is daily making progress is its mission of identifying all 100,000 human genes--and has already found the defective genes associated with a number of diseases, including cystic fibrosis. Once the problem genes have been identified, scientists can turn their efforts to replacing, eliminating or repairing them. They thus hope to develop treatments for much of what ails humanity: from diabetes to migraine headaches, from obesity to cancer.
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But it’s a long way from identifying a gene to finding a treatment, as the cystic fibrosis case shows. Genzyme Corp., a Cambridge, Mass., biotech company, was one of the first to tackle the disease, which causes the lungs to fill up with mucous. The firm first developed the genetic sequence that is missing in the gene that causes cystic fibrosis. The idea was to deliver this piece of genetic “code” to the lungs via an inhaled aerosol spray.
To accomplish that, the gene must be housed in what’s called a vector, usually an altered virus that has the ability to “infect” the host cell. For cystic fibrosis, Genzyme is using an adenovirus--the same kind of virus that causes the common cold--because it can be transferred easily to the lungs.
After several years of laboratory testing, the company has now given the product to about a dozen people, primarily to test for safety, says Gail Maderis, Genzyme’s vice president and business manager of gene therapy. These first trials have introduced the product into nasal tissues to measure whether the replacement gene is “expressing,” or turning on.
The results have been mixed: The gene expresses, but the effect lasts only a few weeks, so the treatment must be repeated. And the repeat treatments with adenovirus activate the body’s immune system, which in this instance is undesirable. So Genzyme must continue altering the virus--or consider using a different delivery system that might be less efficient.
As it tackles these various problems, Genzyme must adhere to a range of regulatory requirements intended to guard against any possible release of an altered gene or virus. Maderis says patients undergoing the treatment must be in hospital isolation the entire time with “every fluid (from their bodies) analyzed.” In addition, when they actually inhale the gene, they are inside a tent, which in turn is inside a negatively pressurized room.
All of this promises to make gene therapy an expensive proposition. “The cost of developing gene therapeutics will be very high,” Maderis warns. She says gene therapy trials are running about $15,000 to $20,000 per patient--more than three times the cost of a conventional trial. And that will translate into high price tags for gene therapy when it is commercially available.
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Many in the industry say that not enough is being done to tackle collectively the difficulties that are slowing the development of gene therapy. Dr. Gregory Brown, a vice president at the investment bank Vector Securities International in Deerfield, Ill., notes that it would make sense to develop vectors that could work for many different treatments. Because any single genetic disorder is usually very rare, Brown says, there often are not enough potential buyers of a drug to justify the enormous cost of research and development.
Further, in the rush to claim ownership of genes and vectors, many of the companies and government agencies involved in genetic research want to compete with one another rather than work together. Blaese reports that to conduct one gene therapy experiment at his own lab, “I have to go to six or eight or 10 different owners of pieces of the puzzle, and the companies involved don’t want to talk to each other.”
One group that’s trying to deal with this problem is Rhone-Poulenc Rorer Inc.’s RPR Gencell alliance, formed last November. The French drug company, with U.S. headquarters in Collegeville, Pa., assembled 14 companies and research organizations to tackle cell and gene therapy discovery and development.
“It is clear that a variety of technologies--a toolbox, if you will--are required to re-engineer biopharmaceutical discovery and development,” says Robert Cawthorn, chairman and CEO of Rhone-Poulenc Rorer. He describes RPR Gencell as “an integrated network of external and internal scientists who will share the tools and expertise necessary to build successful cell and gene therapeutics on an accelerated timeline.”
Through the end of 1994, Rhone-Poulenc Rorer had invested $300 million into Gencell, according to spokesman Bob Pearson, with another $100 million planned this year. But many, many more such efforts will probably be needed if gene therapy is to reach its potential. Though about 60 gene therapy trials are under way, says Rachel Leheny, biotechnology analyst for Hambrecht & Quist, all are still in their early stages, and commercial gene therapy products are not likely to emerge until the turn of the century.
“This has enormous potential,” Blaese says. “We are working with very crude tools, but at least the technology of gene transfer has progressed to the point where it allows us to do things that have a chance of being successful.”
