Major Pharmaceutical Companies Infuse Needed Capital Into Gene Therapy Research

Sidebar: Major Pharmaceutical Companies Are Diving Into the Gene Therapy Pool As gene therapy enters its sixth year of high-visibility research, major drug companies are buying in, helping lay the technology's foundation and launching clinical trials. More than 100 gene therapy trials-most privately funded-are under way. And while the field's ultimate success is still quite uncertain, one thing is clear: There is a lot of science to be done and research opportunities to be pursued. ACADEMIA, INDUSTRY UNITE: Jack Roth of U. Texas M.D. Anderson Cancer Center lauds drug firms' investment. "It seems like there is a new company announcing a gene therapy project every week," says James Barrett, chief executive officer of Genetic Therapy Inc. (GTI), a publicly held biotechnology company in Gaithersburg, Md. "There is a whole wealth of opportunity for scientists." BUSTLE: James Barrett notes that gene therapy provides "a whole wealth of opportunity for scientists." About 4,000 diseases are caused by inborn damage to a single gene. The most common is cystic fibrosis (CF). Cancer, AIDS, and many other acquired illnesses result from a malfunction in one or more genes. Gene therapy aims to cure disease by delivering missing or corrected genes directly to the body. The three diseases-CF, cancer, and AIDS-top gene therapy researchers' current hit list. Most CF investigators hope to inject a missing gene into patients. Many cancer and AIDS researchers want to slip a "suicide gene" into infected cells, causing them to self-destruct or be eaten by the immune system. In each situation, scientists are in early clinical trials. GTI is one of the first biotechnology companies to launch gene therapy trials, in an attempt to treat glioblastoma, a deadly brain cancer, with a gene-drug combination causing tumor cells to self-destruct. The United States Food and Drug Administration-approved trials are now in Phase II. The company has five other Phase I and II trials in progress, including treatments of CF and Gaucher's disease, caused by a rare enzyme deficiency. As of last summer, 13 firms had won approval from the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health to run 34 gene therapy trials. NIH currently requires any DNA research sponsored by an institution receiving federal financial support to be approved by RAC. Many gene therapy firms contract with university researchers to develop RAC-approved technology. Meanwhile, more than a dozen other companies, solely funded by industry, have trials approved by FDA. Chiron Viagene Inc. of San Diego has a gene therapy treatment of HIV in Phase I/II trials, looking at both safety and efficacy. Introgen Inc., a fledgling private company in Austin, Texas, is beginning five trials for cancer. Cambridge, Mass.-based Genzyme Corp. has several trials for cancer and CF. Despite this flurry of activity, researchers and industry observers warn, gene therapy is just that: a trial. Only a handful of peer-reviewed journal articles testify to the technology's safety and potential. Most clinical trials are in Phase I, where safety, not efficacy, is the major focus. And recent media reports (for example, G. Kolata, New York Times, July 25, 1995, page C3) suggest even those clinical trials lack sufficient background research. "A few years back, gene therapy was new and sexy," acknowledges Douglas J. Jolly, vice president of scientific affairs at Chiron Viagene. "People in the field may have had overblown hopes and transmitted them to others. But I believe the field is progressing." Jolly is not the only one who sees progress. Frost and Sullivan, a market research firm in Mountain View, Calif., specializing in high technology, estimates that at least 10 cancer gene therapies will reach the world market by the year 2000. Based on that estimate, the firm predicts the gene therapy market will top $2 billion by the year 2000. Over the past five years, estimates Michael Murphy, editor of the California Technology Stock Letter, companies have spent about $250 million on gene therapy R&D. When a product gets approved, he says, the payoff in annual sales will probably be 10 times that. Meanwhile, research opportunities abound. "There are roughly 100,000 human genes," notes Murphy. "So far, about 2,000 seem useful as therapeutic or diagnostic targets. Every one of those genes is a potential product. There is enough work to keep everyone busy for ages." POTENTIAL PAYOFF: Michael Murphy estimates that firms stand to earn 10 times their current $250 million investment in annual sales. For all of these reasons, major drug corporations have their eyes-and pocketbooks-on biotechnology companies doing gene therapy. Viagene Inc. was purchased in May by Chiron Corp., a biotechnology company in Emeryville, Calif. A few months earlier, Chiron itself had been partially purchased by Switzerland's Ciba-Geigy Ltd. Meanwhile, the Swiss pharmaceutical giant Sandoz purchased GTI and part of SyStemix, a Palo Alto, Calif., biotechnology firm that does both cell and gene therapy. At least eight other drug companies have dropped significant dollars into gene therapy. The most comprehensive investment activity has come from French company Rhöne-Poulenc Rorer (RPR), which has spent $400 million building a partnership network with 14 French and American companies and research institutions doing gene therapy. The so-called RPR Gencell network, based in Collegeville, Pa., is now conducting nine gene therapy clinical trials. Most are in Phase I or II. However, one RPR partner, Applied Immune Sciences Inc., a publicly held Santa Clara, Calif., firm, is in Phase III trials (testing the therapy on a large sample) with a treatment that primes a patient's immune system to attack kidney cancer cells, which could lead to an application for regulatory approval. "We're creating an infrastructure similar to the electronics business," explains Josef Bossart, vice president of business and marketing development for RPR Gencell. "Sony, for instance, is able to go from TV to videocassettes because they've got a basic core of technology that they can take in any direction. Our network is the same kind of core. No matter what the gene discovery, we will have the tools to develop the therapy." Scientists at the interface between academic labs and their corporate partners are especially grateful for the recent surge in investment capital. "None of the clinical trials Introgen is doing would have been possible without Rhöne-Poulenc," says Jack Roth, Introgen's chief scientific adviser and a professor of tumor biology at the University of Texas M.D. Anderson Cancer Center. "It's difficult to get NIH or foundation funding to translate experiments from the lab to the clinic. It's fantastic that pharmaceutical companies have picked up the slack." CAUTIOUS OPTIMISM: Steven Rosenberg notes the importance of open communication between academic scientists and industry. Other researchers express cautious optimism about industry interest in gene therapy. "An enormous amount of work in gene therapy needs to be done," comments Steven Rosenberg, chief of surgery at the National Cancer Institute. "In an era of decreased federal funding, I think interest by biomedical companies can be useful. So I see it as a positive step. It's very important, however, that information continues to be open between industry and academic scientists. Communication sometimes suffers because the rules of business precede the rules of science." Gene therapy began in earnest with one bubbly four-year-old. In 1990, young Ashanti DeSilva became the first patient to undergo federally approved gene therapy. Ashanti carries a defective gene that normally produces adenosine deaminase (ADA), an enzyme crucial to the immune system. In 1990, a team of NIH researchers got permission from RAC to insert a normal ADA-producing gene into Ashanti's white blood cells. On four separate occasions, the researchers removed white blood cells from Ashanti, inserted normal copies of the ADA gene, and injected the corrected cells. The experiment appears to have worked (R.M. Blaese et al., Science, 270:475-80, 1995). With occasional follow-up treatments, Ashanti and a second young patient receiving the same treatment (Cynthia Cutshall, who was nine years old at the time and is now 14) have become much healthier. However, both children also receive injections of synthetic ADA. So it's hard to evaluate how much of the credit for their health belongs to gene therapy. Ashanti's success immediately sparked a torrent of gene therapy investment and research. At the time, GTI and NIH had signed a Cooperative Research and Development Agreement (CRADA) granting GTI an exclusive license to commercialize the technology. Similarly motivated venture capitalists and academic researchers collaborated to form gene therapy startups. "These small companies were very focused on a particular approach to gene therapy, depending on their intellectual property," says Brian Huber, director of pharmacology and molecular therapeutics at Glaxo Wellcome Inc., a pharmaceutical company based in Research Triangle Park, N.C. "Now, with pharmaceuticals coming in, the field is really beginning to open up. For scientists, I think the best opportunities lay in vector design and development." Essentially, physicians perform gene therapy using an ex vivo or in vivo approach. In Ashanti's case, researchers used the ex vivo method. The most popular ex vivo way to deliver genes is through a retrovirus vector, or carrier, that targets rapidly dividing cells, such as cancer cells. Scientists start with a disarmed mouse-derived retrovirus, spiking it with therapeutic genes and injecting the modified virus into a patient. Many gene therapy trials involve loading tumor cells with a gene that produces a protein recognized by the immune system. The system should respond by wiping out the cancerous cells. A similar approach is aimed at destroying cells infected with HIV. But ex vivo therapy is complicated and costly. Most researchers agree that as gene therapy evolves, in vivo use will emerge. Right now, the most publicized in vivo approach is the use of an adenovirus vector to shuttle a missing-chloride ion-processing gene into the mucus-filled lungs of CF patients. Although the method has yet to work, researchers say they are making significant progress. Viral vectors are tricky, investigators say. They often generate poor gene expression, forcing researchers to administer repeat doses, which are expensive and can irritate tissue. Plus, adenoviruses, which normally cause a cold, are hard to sneak past the immune system, whose marauding cells kill the viruses-and their genetic payload. "We're still developing an ideal way to deliver genes," acknowledges Gary McGarrity, vice president of development at GTI. According to McGarrity, GTI currently supplies a mouse-derived retrovirus vector for more than 40 clinical gene therapy protocols. STEPS TAKEN: Despite the public's past "overblown hopes," Douglas Jolly is optimistic. A host of companies provide the genes, vectors, or instruments needed to make gene therapy work. Each of these, notes McGarrity, is a potential employer of molecular-minded researchers. RPR's Bossart observes: "It's an exciting time for scientists. In gene therapy, you need a lot of specialties. You need people who know retroviral vectors, people who know adeno-associated vectors, people who know genomics. Even in the big companies, you will find they are bringing together a lot of little specialties." Pushing gene therapy products from concept to market remains a largely untraveled path. So far, McGarrity says, FDA has been proactive in helping companies launch clinical trials. About 600 patients are currently participating in gene therapy trials. A number of business issues challenge gene therapy's entrepreneurs. What will the final product be? Will health insurance cover gene therapy treatments? How much will they cost? How will the field market itself? And what will bioethicists say? One classic business struggle has already ruffled a few feathers: patents. Early on, GTI filed for a patent on all ex vivo therapy. The company won the patent-and the ire of many researchers, who believed GTI was being greedy or unfair. And in August, a federal appeals court in Virginia allowed Genentech Inc. of South San Francisco, Calif.-in a dispute with Chiron-to retain patent rights over a blood clotting factor being investigated for its potential use in gene therapy. Still, researchers agree, it's really the science, not business snags, that challenge gene therapy. "The real players in gene therapy will be the ones who find a clinical need and quickly develop the proprietary technology to fix that need," says Huber. With that in mind, he adds, the opportunities for scientific creativity are limitless. Sidebar: Major Pharmaceutical Companies Are Diving Into the Gene Therapy Pool Kathryn S. Brown is a freelance science writer based in Columbia, Mo.

Major Pharmaceutical Companies Infuse Needed Capital Into Gene Therapy Research

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