Bridge Over Troubled Waters

Crossing to safety and efficacy in gene therapy is current challenge

by Margaret Wahl on January 1, 2005 - 3:54pm

The year was 1990, the place the Warren G. Magnuson Clinical Center at the National Institutes of Health in Bethesda, Md. Four-year-old Ashanthi DeSilva of North Olmstead, Ohio, born with a devastating genetic disorder of the immune system, was to be the first person to undergo gene therapy — the insertion of therapeutic genes to treat a disease. (Newer forms of gene therapy developed since then involve changing how cells interpret genetic information.)

Ashanthi’s gene therapy was an ex vivo (outside the body) treatment. The gene for the ADA enzyme, which she was missing, had been inserted into blood cells taken from her circulation. These cells, now carrying new genes, were reinfused into the little girl in this first human gene therapy experiment.

The treatment was found safe, and ultimately proved moderately successful, although its overall contribution to Ashanthi’s health was hard to measure because she continued to receive another treatment at the same time.

Nevertheless, this first gene therapy was a shot heard ‘round the world. By the early ‘90s, everyone, it seemed, was talking about the promise of gene therapy, for everything from rare genetic disorders like muscular dystrophy to conditions like heart disease and cancer.

In 1986, MDA-backed researchers had identified the gene for the dystrophin protein as the one that’s flawed in Duchenne muscular dystrophy (DMD). In the ‘90s, the genes for nearly all the genetic disorders in MDA’s program were identified, including those underlying several forms of limb-girdle muscular dystrophy (LGMD). Gene therapy seemed an obvious answer to the quest for an MD treatment.

But the path to it would prove more difficult than many expected.

As gene therapy trials in a range of diseases were proposed, regulatory agencies and consumer groups swung into action. Their main concerns weren’t whether gene therapy would be effective, or even safe, for the person receiving it. Rather, they examined broad ethical questions about altering the genetic makeup of the population and worries about genes lodging in egg or sperm cells of recipients and affecting the next generation.

These concerns, however, soon faded into the background, as did the excitement about gene therapy.

For most diseases, in vivo (in the body) gene therapy was necessary, because most cell types can’t easily be removed from the person and then reinfused. Genes instead had to be inserted into vectors, or delivery vehicles, such as viruses, and injected directly into the recipient, where it was hoped they would home in on their targets and not go where they might do harm.

Worries shifted from changes to the population’s genome to damage to the body from viruses used as vectors and the overwhelming challenge of reaching the right cells (and only those) with the new DNA.

Shocking setback

In 1999, MDA-supported investigators began a clinical trial for sarcoglycan-deficient LGMD. The purpose of the trial was to assess the safety of injecting into a foot muscle an adeno-associated virus (AAV) vector carrying a gene for a sarcoglycan protein.

But after only two participants had received gene injections in the LGMD study without ill effects, an 18-year-old man participating in an unrelated gene therapy trial for OTC deficiency (a metabolic disorder) unexpectedly died within four days of a gene therapy injection. The young man had received OTC genes wrapped in adenoviral vectors (different from AAV) and injected into an artery going to his liver (different from muscle injection).

Gene therapy researchers were stunned. The public was outraged. Regulatory agencies were asked to explain how this could have occurred. It would be several years before the field would resume its previous momentum, and there would be more bumps in the road ahead.

In 2002 and 2003, two children out of 10 treated with gene therapy for an immune-system deficiency disease developed leukemia, which was eventually traced to the way a retroviral vector had inserted itself next to a cancer-causing gene. Retroviruses, even after alteration, are capable of such insertions, gene therapists learned.

A promising trial of gene therapy for hemophilia using an AAV vector was stopped because indications of liver damage in one participant were interpreted as a possible reaction to the virus.

And clinical trials using AAV vectors for gene therapy in the lung disease cystic fibrosis have shown that the strategy, while apparently safe, so far hasn’t been effective.

All gene therapies aren’t alike

R. Jude Samulski

For R. Jude Samulski, a virologist and gene therapy specialist at the University of North Carolina at Chapel Hill and the biotech company Asklepios BioPharmaceutical (see R. Jude Samulski), the main problem is that “the field of gene therapy got lumped into one.”

Technically, Samulski says, gene therapy research is “as diverse as all the drug companies that exist today. You wouldn’t call Glaxo, Merck, Pfizer and Novartis the same company, because they all do different things, and they do it in different ways. But the field of gene therapy was considered one.”

In the gene therapy world, he says, “What people don’t appreciate is that the different vectors that were being tested in the early days were all very experimental. They were all being driven by the science generated over a number of years by different groups, and they represented in essence different core technologies.”

As critical as Samulski is of the heavy artillery that’s been aimed at gene therapy, he’s equally critical of the exaggerated promises that surrounded its early days. It can take as long as 20 years to move a good idea from the laboratory to the clinic, he says, citing the example of monoclonal antibodies, immune-system molecules developed to kill cancer cells and stop inflammatory responses with high specificity. These first emerged in labs in the mid-1970s, he notes, but the first treatments based on them weren’t seen until the late 1990s.

“All these things are becoming real, marketable products that are changing people’s lives,” he says, pointing to the breast cancer drug Herceptin and the colon cancer drug Erbitux. “But the science said it was going to happen 10 to 20 years ago.” Moving from the academic setting through the regulatory process and finally into the commercial pipeline takes that long, he says.

New beginning

While heeding the risks inherent in gene therapy, MDA researchers have forged ahead in creating new vectors they believe will be safer and more effective than old ones. Along with newly miniaturized genes for dystrophin and, in some cases, entirely new methods of gene delivery without viruses, this updated information has renewed the promise of gene therapy in neuromuscular diseases.

The challenge now — almost 20 years after the identification of the first MD gene and 15 years after the first human gene therapy experiment — is to move out of the lab and into the clinic to test not only safety but efficacy of gene therapy systems.

“It’s matching the right disease with the right vector and the right gene,” Samulski says. “It’s not simply one component. It’s all three. We’re really going through a trial-and-error process.... I think that’s accepted in every other drug development setting.”

Dusty Miller, a molecular biologist working on gene therapy for cystic fibrosis at the Fred Hutchinson Cancer Research Center in Seattle, sees a need to move to human trials, even if some risk is involved.

“It could be that mice are not predictive of humans,” he says, recalling instances in which gene therapy appeared effective and safe in rodents but didn’t prove so in people. “In mice, type 6 AAV looks less immunogenic [provoking to the immune system] than type 2 AAV,” he says of current experiments. But at some point, he says, “you have to address the biology in people.”

Although MDA’s gene therapy program, like many others, has been stalled by unexpected scientific and regulatory obstacles, the program is now back on track, with three front-running, MDA-supported groups racing toward human trials in Duchenne dystrophy.

Each group hopes to have the winning combination that will make gene therapy for DMD safe and effective. That would mean a vector that elicits little or no immune response and causes no other adverse effects, a gene that provides a recipe for a dystrophin protein that’s almost as good as the one nature provides, and a way to deliver enough dystrophin to halt or even reverse the muscle damage in DMD.

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