Gene therapy shows signs of success after years of hype; Synthetic genes helping patients with 2 diseases


At 16 months of age, curly-headed Max can reach out and grab a toy. With his eyes he can follow his mother, Ilyce Randell, as she walks around their home in Palatine, Ill.

For a child with Canavan's disease, a rare neurological disorder that starts unwiring the brain after birth, Max wasn't supposed to be playing with toys and smiling at the sight of his mother. The defective gene he inherited wipes out thinking, feeling, emotions, vision and muscles.

But Max has millions of copies of a healthy gene implanted in his brain to do the job that the defective one has failed to do.

"He had very little mobility with his arms before he was treated, and he couldn't see very much at all," said Randell. "It's very encouraging."

Not far from the Randells, Cynthia Yannias of Palatine is eagerly following a gene therapy experiment to cure Gaucher's disease.

That experiment also is producing promising early results, and if the therapy works, Yannias' 3-year-old daughter, Valerie, will be on the list to receive a good gene to replace the dysfunctional one that has given her Gaucher's disease.

Gaucher's disease, which causes deadly cellular debris to build up in the brain, liver, spleen and bone marrow, affects 10,000 to 20,000 Americans.

Right now, Valerie's disorder is being kept at bay by another piece of gene magic. Twice a month she receives 4-hour-long infusions of the product that her dysfunctional gene doesn't make, an enzyme that removes cellular debris from vital organs.

But at $10,000 a month, the enzyme, which is made from a human gene transplanted into the ovaries of Chinese hamsters, is expensive.

The Canavan and Gaucher experiments represent the first ray of light that gene therapy, after nearly 10 frustrating years of failures, may be coming of age -- that it can undo the damage of defective genes and free people from devastating inherited diseases.

Scientists warn that more work is needed to prove that the therapies are effective, but many in the field believe a milestone has been reached.

Few breakthroughs in medicine have been greeted with greater anticipation than gene therapy. It holds the promise of defeating ancient inherited enemies, such as hemophilia, cystic fibrosis, muscular dystrophy, sickle cell anemia, and Tay Sachs disease, by replacing bad genes with good ones.

It even promises to cure such common genetically linked diseases as cancer, heart disease, stroke and Alzheimer's disease. Once a gene is discovered, it can be made synthetically.

Disappointing experiments

So far, gene therapy hasn't lived up to its promise, despite more than 250 experiments involving several thousand people.

The field was shaken up in 1995 by the National Institutes of Health, which at that time was spending $200 million a year to support gene therapy research. NIH issued a report critical of researchers for making claims that never came true.

Chastised, scientists went back to their laboratories, keeping low profiles while they tried to figure out how to deliver curative genes to people.

Techniques improved as a result of that reassessment, and there is growing confidence that gene therapy may finally be approved for general use in the next three to five years.

Fueling the new feeling of optimism are the early results of the Canavan and Gaucher's gene therapy experiments, along with a third project conducted by Dr. Jeffrey M. Isner of St. Elizabeth's Hospital in Boston.

Isner has reported using genes to grow new blood vessels in the legs of diabetic patients to restore circulation and forestall amputations.

He has also reported using the same genes to grow new vessels to feed the hearts of patients with crippling heart disease, putting them back on their feet.

"The field of gene therapy is certainly feeling better after several years of being in the doldrums," said Dr. French Anderson of the University of Southern California.

In 1990 Anderson and colleagues at the National Institutes of Health performed the first gene therapy experiment, giving a gene that builds a critical part of the body's immune defense system to two young girls who were born without the gene.

The girls suffered from severe combined immunodeficiency disease, which was made famous by the boy who lived in a protective "bubble" in a Texas hospital until he chose to walk out. He died of an infection a short time later.

The two girls were being kept alive by infusions of the enzyme made by the gene they were missing. Anderson's team put the gene into their white blood cells, hoping the girls could make their own enzyme.

Although there was some evidence that the healthy genes worked for a while, the experiment failed to prove that gene therapy could cure the disease.

The next step came in 1995 when Dr. James M. Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania in Philadelphia, showed that he could remove liver cells, put in a gene that lowers cholesterol, and give the cells back to patients with life-threatening cholesterol levels.

The genetically engineered liver cells worked like a charm, but the experiment came to a dead end. Not enough liver cells could be removed from a patient and genetically re-engineered to alter the course of the disease.

The delivery roadblock

The main roadblock to gene therapy has been the inability to devise an effective means of delivering genes to target cells so that they take hold and survive for the life of the cell.

Viruses are a favorite delivery vehicle. Viruses can be emptied of their own genetic cargo, making them harmless, but their ability to enter cells is preserved. Scientists pack human genes into the empty viral shells, and use them in studies of inherited disorders.

"Over the next 18 months, we will see the definitive proof that gene therapy works to cure patients," Wilson said. "Over the next few years we will see the first commercialization "

Ilyce Randell believes she is seeing some of these wonders already in her son, Max.

When Max was born, his parents noticed that he was extremely unresponsive, and he wasn't developing. They thought he might be autistic.

"He wasn't hitting any of the milestones," Randell said. "He didn't notice toys. You'd shake keys in front of his face and it was like he didn't see them. He was like spaced out, and not really part of the world at all."

Still profoundly disabled, Max now plays with toys. His favorite has a big yellow button that plays music and moves an animal when he pushes it.

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