The tally is grim: three high-profile cancer cases, including one death, in French boys who underwent pioneering gene therapy for X-linked severe combined immunodeficiency (X-SCID). Yet Edward Lanphier is upbeat about the future of gene therapy.

"It's a very, very broad field," says Lanphier, CEO of Sangamo BioSciences, a Richmond, Calif., biotechnology company focused on gene regulation. "It's sort of like saying there's been an awful auto accident, is there a future for the transportation industry? Is there a future for gene therapy? Categorically yes. Will companies pursue this from a commercial perspective? Categorically yes. And the outcomes in France in some of the SCID trials, as tragic as they are, are extremely informative."

Lanphire was reacting to the latest setback in a field that has experienced dramatic lurches in the last two decades. Gene therapy, once hyped as offering boundless promise by fixing faulty genes, has seen some dark...


Hopes for gene therapy soared in 2000 when Marina Cavavazzana-Calvo and Alain Fischer of the Necker Children's Hospital in Paris reported successfully using gene therapy on children afflicted with X-SCID. However, a boy treated by Fisher was diagnosed with a leukemia-like cancer in September 2002, and a second boy was diagnosed three months later. One of the boys died in October 2004, and a third was diagnosed in early 2005. Other children who are now free of X-SCID because of the treatment, including some in France and the UK, are being monitored. In late January, the Food and Drug Administration suspended three similar gene therapy trials in the United States.

Jean-Yves Bonnefoy, chief scientific officer of Transgene, a biotechnology company based in Strasbourg, France, says his company has largely moved away from gene therapy, although the move pre-dates the French cases and has more to do with seeking a larger market. "The problem with gene therapy is the targeting and delivery vehicle," say Bonnefoy, worked with Fischer in the early 1990s. "How can you make sure it targets only the cell you want?"

Other high-profile gene therapy cases have not helped, such as the death of teenager Jesse Gelsinger in a 1999 trial at the University of Pennsylvania. Some experts say his death was due to the high number of viral particles infused during the trial, rather than the gene therapy itself.


Photo: European Press Agency

Child with severe, hereditary immune deficiency at Debrousse Hospital in Lyon, France.

All this has investors cautious about betting on gene therapy. Navdeep Jaikaria, director of equity research for the New York City investment firm of Rodman & Renshaw, says companies targeting a narrow spectrum of the field may be successful, although gene therapy has "definitely fallen out of favor with investors."

"You can measure that by the value gene therapy companies are enjoying compared to other similar-stage biotech companies. They are trading as a group at a 30% to 40% discount," Jaikaria says. "Avigen recently announced that it is discontinuing its gene therapy program."

However, the situation could change rapidly. "Any success can bring investors back. We like companies addressing unmet medical needs like cancer and cardiovascular disease, because the risk-reward profile is such that the FDA is willing to look at novel therapies," says Jaikaria. "We view gene therapy to be no different from any other drug delivery platform, but there are questions which keep investors concerned."

Jaikaria says companies focusing on short-term gene therapies show commercial promise. "There are two kinds of gene therapy, if you can say that in a simplistic manner. One is you put a gene into a cell and it doesn't integrate with the genome of the individual, and that's what GenVec and Coratus [Genetics] and several other companies are trying to do. The other form of gene therapy is trying to correct a deficient gene in a cell, and we don't really see that kind of gene therapy succeeding commercially in the next five to 10 years. But GenVec, Coratus, Targeted Genetics, Sangamo – we think they have promise and their programs can succeed."

Genzyme's Gregory says the French clinical trials have caused a public-relations problem for gene therapy in general, and they have affected small companies' ability to raise money. "It's tough for companies in the gene therapy space to raise additional funds because of the general impression in the venture capital community that gene therapy is not the place to be," Gregory says. However, the trials have had less impact on Genzyme, which has a long-term commitment to gene therapy and still sees it as a therapy of the future. "For us, it's been steady, hold-the-course, but I can see there are certainly fewer companies in the gene therapy space than there used to be, and my impression is it's tougher for those companies."

Others are having success with alternative approaches. Sangamo BioSciences recently announced it had achieved the highest expression levels to date of the IL2R-gamma receptor gene in cultured cells by using engineered zinc-finger DNA-binding proteins fused with endonucleases. Correction of the IL2R-gamma receptor gene, which is mutated in X-SCID, was achieved in about 18% of cells. The technique could avoid the insertional mutagenesis that can be caused by using a viral vector (see related story, page 20). The report was published in an advanced online version of Nature and presented at the annual meeting of the American Society of Gene Therapy (ASGT)in April.12

The Sangamo research team hopes to isolate stem cells, use the technique, and reintroduce the cells into the patient, although more work needs to be done to determine if the procedure is safe and effective. The team also plans to use the technique to treat other illnesses. "It's a very powerful technology we can apply to any gene in the genome, and we have active programs across the board: neurological, cancer, ophthalmic, and more," says Lanphier. The company's technology3 is quite different from the technology used by the French researchers, he says. "We're part of a whole mosaic. There are many different approaches lumped under the general heading of gene and cell therapy."

Sangamo and its corporate partner, the Irvine, Calif.-based medical device company, Edwards LifeSciences, are conducting Phase II clinical trials at the National Institutes of Health in Bethesda, Md. They are using the technology to spur new blood vessel formation, potentially increasing blood flow to the heart and legs. The company is also attempting to repair mutant genes as well as disrupt genes to treat illnesses such as sickle cell anemia and HIV.



Sangamo BioScience's technology is based on DNA transcription factors called zinc finger DNA-binding proteins, or ZFPs. The DNA recognition and binding function of ZFPs can be engineered and thus directed to any DNA sequence permiting delivery of a variety of functional domains to gene-specific locations.

Other companies are using gene therapy as a temporary form of drug delivery. Paul Fischer, president and CEO of GenVec in Gaithersburg, Md., says the company is focusing on temporary protein replacement to treat a variety of illnesses. "Our thought was that with many important diseases like heart disease, cancer, and blindness, if you could temporarily express a protein, you could have a big impact, but not have to worry about the long-term expression of that protein."

The company is now in Phase II clinical trials of a product called TNFerade, which delivers the tumor necrosis factor-alpha (TNFa) gene via an adenovirus vector to patients getting chemotherapy and radiation therapy. The product, which is replication-incompetent, is directly injected in tumors with the goal of stimulating TNFa production. "It's just temporary, it's not incorporated in a patient's DNA," says Fischer.

GenVec and the Miami Lakes, Fla.-based medical device-maker Cordis are also conducting Phase II clinical trials on a drug that promotes the growth of new blood vessels in patients with poor blood flow to the heart, says Fischer. "That's another example of using a gene to express this VEGF (vascular endothelial growth factor) protein a little while, one or two weeks, and that's enough to start the formation of new blood vessels."

GenVec is also in Phase 1B clinical trials for a gene therapy product targeting the sight-robbing condition, wet macular degeneration. "If you can locally produce one of these proteins – in the eye, the heart, or the tumor – then the protein can do its job better," says Fischer, "but it doesn't cause toxicity because it doesn't get into the bloodstream."

Targeted Genetics, a Seattle-based company, also has a couple of gene therapy products in Phase I trials. The company's lead product is an AIDS vaccine candidate called tgAAC09, which consists of a select HIV gene packaged in an adeno-associated virus capsid. It is in early trials in Europe and India, with plans to expand into high-risk groups in sub-Saharan Africa, says Stewart Parker, president and CEO of the company.

Targeted Genetics is collaborating with the nonprofit International AIDS Vaccine Initiative and the Columbus Children's Research Institute (CCRI) in Ohio. The results of the Phase I trials, due in the second half of 2005, will "tell us how far we can go," says Parker. Also in Phase I clinical trials is the company's other main program, a gene therapy product targeting inflammatory arthritis.


<p>Alain Fischer and Marina Cavazzana-Calver</p>

Photo: European Press Agency

Overall, investment experts see more interest in gene therapy compared with a few years ago. For example, Alta Partners, a San Francisco life sciences venture capital firm, last summer raised $32 million for Ceregene, a San Diego-based startup focusing on treatments for Alzheimer and Parkinson diseases, as well as other ailments.

"Two years ago, if you were a gene therapy startup looking for institutional funding, it would have been hard to get funded," says David Mack, a director of Alta Partners. "That's not to say it's easy today. It's really hard. But it's happening," says Mack. "It's not like gene therapy is hot. It isn't. But once we see a major clinical success, people will say that in the right circumstances, this is the correct therapeutic strategy. Unfortunately, empirical learning runs throughout the process. We saw it in antibodies. That went through a similar type of crash-and-burn process. But gene therapy is not one thing. One thing comes to mind, but it's literally hundreds of different strategies."

Savio Woo, professor and chairperson of gene and cell medicine at the Mount Sinai School of Medicine in New York, notes that without treatment the children in Alain Fischer's trial would have either died or lived their lives in a sterile environment. "These children were able to go home and live with their families," Woo says. "Think of it. You have a dozen patients whose prognosis is death, and after gene therapy, they were able to go home and live with their families. By any other measure, I'd call that a miracle."

He says other scientists are making exciting gene therapy discoveries. For example, Jean Bennett of the University of Pennsylvania is having some success using gene therapy to treat dogs with congenital blindness. She is treating one eye and using the other as a comparison, says Woo. "She has a bunch of dogs walking around with their heads tilted." The treatment could help people who are born blind, he says.

Still, the three French cancer cases mean "everybody's worried," says Woo, who is also past president of the ASGT. "The challenge to the research community is to come up with better ways for gene delivery so we can deliver the gene in safe ways that would not cause leukemia." While the public may think gene therapy causes cancer, "it's just a small slice of gene therapy."

Mark Kay, president-elect of the ASGT, says part of the problem is that gene therapy is taking longer than expected to deliver treatments. The field started to flourish in the late 1980s and early 1990s, and the promise is still unfulfilled. "It's going to take time, but most people knowledgeable about the field are confident it will succeed at some point. Part of the issue with companies is they want a quick turnaround, and because it's taking longer than anticipated, some of them don't want to wait."

"Ten to 15 years ago, the expectations were sky-high [for gene therapy]. It was over-hyped," says Woo. "Today, we're not getting due credit. The French cases to some are a death knell, but to me it's a miracle. I'd say the truth is in-between."

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