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Gene Therapy Undergoes a Reevaluation

November 12, 2002|Rosie Mestel | Times Staff Writer

Gene therapy has become a science of irony and unintended consequences.

Through its decades of development, the once-glamorous child of the genetic revolution has faced bad press, lackluster results and a tragic death. Now, fast on the heels of its first-ever success -- and one of its biggest disappointments -- the field is having to reevaluate its use of a principal method of inserting therapeutic genes into cells.

The upheaval has placed new emphasis on a range of experimental strategies that hold great promise but are technically difficult and will take even more time to become useable in the clinic.

Those strategies include ways to control the placement of therapeutic genes so they don't damage the genome, implement precise DNA repair methods so no new, potentially dangerous genetic information is added to a patient, and create "suicide" genes that are programmed to wipe out genetically altered cells if anything should go wrong.

The cause of the upheaval is one small child. Not long ago, researchers were reveling in the apparent cure of nine French children afflicted with the rare immune system disorder, X-SCID, commonly known as "bubble boy" disease. Then, a few weeks ago, the researchers announced that one of the children has leukemia -- caused, they suspect, by the therapy itself.

Risks that were once only theoretical have become real. Promising strategies that seemed to overcome enormous hurdles may have to be scrapped. Concerns by some scientists and bioethicists that the endeavor has moved too quickly to the clinic have found a more emphatic voice.

"This is definitely an attention-getter, a wake-up call for everybody, and we need more information," said Dr. Kenneth Weinberg, professor of pediatrics at USC and a physician at Childrens Hospital Los Angeles.

Many scientists still see ultimate promise for the gene therapy. But they cannot predict its fate for the foreseeable future: whether it will be only a niche science for the treatment of the most extreme diseases for which sizable risks are worth taking or, as scientists have long envisioned, a broader strategy for tackling a range of ills, from blindness to baldness.

"At the very best, it looks like this will add years and years to the clinical development of gene therapy," said Dr. Alan Schechter, chief of the laboratory of chemical biology at the National Institute of Diabetes and Digestive and Kidney Diseases.

Gene therapy is a prospect that has long touched deep nerves among the public and magnified both hope and revulsion, causing unrealistic expectations and extreme reactions when things go wrong.

Scientists too were seduced by its clean logic, often rushing too quickly to make promises of cures and then facing a backlash when trials failed.

"There was the impression among some people that it was going to be rather easy. You have the disease, you put in the gene and correction would be pretty straightforward," said Dr. Theodore Friedmann, director of the gene therapy program at UC San Diego. "There was too much hype, too much downplaying of the problems."

Scientists had known for decades that many inherited diseases were because of errors in individual genes. As the genetic revolution gathered momentum -- and scientists learned how to manipulate DNA -- the notion of mending errors no longer seemed fantastic.

Ideally, doctors could correct the genetic error in cells where the gene was required (lung cells, say, in people with cystic fibrosis), leaving the rest of the genome untouched. Such tidy fixes are technically very difficult.

A messier, but easier, strategy is to add a good gene to a cell without getting rid of the faulty one. That's what scientists do in today's gene therapy trials, and what was used in the French case.

Getting a gene to its target isn't easy, so scientists have turned to viruses, which are tailor-made to steal through the body and enter cells. The disease-causing parts of the virus DNA are removed, the therapeutic gene spliced in, and the whole thing wrapped up in the virus coat. Then the hybrid creation is added to the body.

Today, there is a medley of "viral vectors" capable of entering a variety of tissues. Gene therapists pick the ones to suit the disease they're trying to cure, which today includes everything from inherited diseases to HIV infections and cancers.

For some therapies (such as for cancer), a gene doesn't have to stay permanently or be passed on to new cells if the original cell divides. In those cases, a virus that efficiently enters cells but eventually dies away fits the bill.

In other cases, such as inherited diseases like cystic fibrosis, a repair has to be permanent. Here, the use of special viruses that insert their genetic material into cells' genomes ensures that the fix is replicated when cells divide.

Using such methods, researchers have cured mice by the thousands -- of hemophilia and sickle cell disease, of diabetes and cystic fibrosis.

But they have learned, to their pain, that mice are not people.

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