A new setback for gene therapy

Fifteen years ago, researchers thought cystic fibrosis would be the first easy hit of the gene-therapy revolution. The deadly lung disease is caused by a single faulty gene, so, in theory, delivering a properly functioning one into cells ought to cure the disease.

It may happen someday, but yesterday one of the stalwarts of the cystic-fibrosis field, Seattle-based Targeted Genetics, dropped out. In the largest clinical trial ever conducted of gene therapy for cystic fibrosis, with 102 patients, the company failed to reach its goal of helping patients breathe significantly better, even for a month.

The failure is another blow to a field that's seen hype from the early 1990s turn into frustration in recent years.

Earlier this month, the Food and Drug Administration halted some gene-therapy clinical trials because of safety concerns. After 15 years, no gene-therapy treatment has been approved by the FDA for use in the United States. And of more than 100 companies formed to pursue gene therapy, only about 20 remain.

Targeted Genetics' setback comes after 15 years of its scientific work, at least $40 million from investors and partners, and glimmers of hope from preliminary studies. The small biotech company's stock was gutted 35 percent yesterday after the news, falling to 82 cents a share.

The company said it will shift its efforts to gene-therapy experiments for an AIDS vaccine and a new treatment for rheumatoid arthritis, both still in early human testing.

Other opportunities

"As much as we hate it, and as discouraging as it is, this product just doesn't have a future," said H. Stewart Parker, the company's chief executive. "We have other opportunities."

Back in 1994, perceptions of the field were much different. A cover story in Time magazine was titled "Genetics. The future is now," adding that "new breakthroughs can cure diseases and save lives." The technology fascinated people by using tiny modified viruses to shuttle human genes into cells, where the genes could correct genetic malfunctions at the roots of disease.

But five years later, an Arizona teenager died in a gene-therapy experiment, generating intense public scrutiny. Novartis, a giant drug company, sank an estimated $1 billion into gene therapy before pulling the plug.

Even the hopes now come with large caveats. Three years ago, a gene-therapy study in France showed it could restore the immune systems of 10 young children with severe immune deficiencies, essentially curing them. But earlier this month, in connection with that study, the FDA halted some gene-therapy trials after three of the young French patients developed cancer, and one died.

Gene-therapy experts, however, say the latest discouraging news isn't the end of the road for gene therapy.

Dr. Bonnie Ramsey, Seattle-based director of the Cystic Fibrosis Therapeutics Development Network, a consortium of research centers, said Targeted Genetics' studies showed in more than 200 patients its tiny, modified virus was a safe delivery vehicle. She said newer versions of the same virus, developed in the lab, appear to be more effective at delivering an active genetic payload into cells. "We have learned a lot," she said.

For cystic-fibrosis patients, Ramsey said, she's optimistic other treatments will work, like reformulated antibiotics or conventional chemical drugs.

Fear of side effects

Dusty Miller, a gene-therapy researcher at the Fred Hutchinson Cancer Research Center, said the fear of serious side effects in clinical trials has made the FDA more cautious. The regulatory hurdles have discouraged some young researchers from entering the field.

Still, he said, there are 10 principal researchers in gene therapy leading teams in Seattle, including a national Center of Excellence at the University of Washington. The National Institutes of Health spent $37 million on gene-therapy clinical trials in 2004, and expects to spend about the same this year and next.

The number of new applications to do gene-therapy trials rebounded to 56 in 2004, according to the FDA.

Darin Weber, a consultant with the Biologics Consulting Group in Seattle and a former FDA reviewer of gene therapies, said there were 190 ongoing or proposed gene-therapy clinical trials in the U.S. in 2003.

Some pharmaceutical companies have backed out of the field; about 56 percent of the applications were from academic researchers, and the rest from biotech and pharmaceutical companies.

One of the key challenges is finding a modified virus, a so-called viral "vector," that can effectively deliver genes inside cells. Some new vectors have shown 100-fold greater rates of genetic transfer into animal cells than did older vectors, like the one used by Targeted Genetics since the early 1990s.

Moving from gene transfer in animals to humans also has proven extremely difficult. Targeted Genetics used an inhalation device to deliver its gene therapy directly to the lungs. It has had difficulty showing its gene therapy arrived inside cells and began functioning there. An early, smaller study, however, showed some signs of improved breathing ability in patients after 30 days, but the ability diminished over time.

A different vector

Miller, a scientific co-founder of Targeted Genetics who is no longer associated with the company, said he's trying a different vector for cystic fibrosis that may release genetic cargo inside cells more effectively.

The hope for gene therapy, many scientists now believe, has moved away from genetic diseases and more toward diseases acquired later in life, like cancer or heart disease. One reason for the shift is that patients with those diseases may be willing to accept greater risks, Miller said.

Much of the responsibility to move the field ahead will lie with academic, government-funded researchers, because private investors have been scared away, he said.

"The public has to understand that if they want these treatments, there's a certain amount of risk," Miller said. "It's a matter of weighing risk, benefit and cost."

Some biotech companies also have tried to distance themselves from the field because of the high-risk connotations, calling their gene-therapy work by other names. But Parker said about 20 biotech companies are still working on gene therapy.

Parker would not predict when people might expect the first gene therapy to arrive on the market. She said it could be soon for cancer, where some trials are in the final stages.

Until a success story emerges, she said, the failures of gene therapy will be amplified.

"We just need to keep our heads down and keep working," Parker said.

Luke Timmerman: 206-515-5644 or ltimmerman@seattletimes.com