• 1/19/2005
  • Robert Cooke
  • Newsday.com – Health/Science

The experiment was daring – squared. Two brave little Ohio girls underwent the world’s first authorized gene therapy experiment – an attempt to give them functioning immune systems for the rest of their lives. The procedure delivered new, corrective genes into their white blood cells, using a virus as the delivery vehicle.

That was 15 years ago. Today, both are college students. Without those new genes, it was unlikely they could have survived in a world of germs – even if sheltered inside huge plastic bubbles.

Their survival signaled the advent of a promising frontier, one designed to repair genetic flaws behind life-threatening disorders. But after 5,000 patients had participated in 350 trials, things began to go wrong.

First, in 1999, a young man being treated by the University of Pennsylvania died of a massive immune reaction to the gene treatment for a rare metabolic disorder. Three years later, a French baby was successfully treated for the same disorder the Ohio girls had, but developed leukemia as a byproduct of the treatment. The next year, a second French child did likewise. Researchers called a timeout.

Today, a leading researcher says those downturns have provided a reason for optimism: They taught valuable lessons and, as a result, gene therapy is poised for a renaissance.

The expert, Dr. Savio Woo, said that today researchers not only understand what triggered leukemia in the two children, but also are emboldened because the therapy itself has proven a success. The two children’s condition – severe combined immunodeficiency, or SCID, but commonly known as bubble boy disease – was cured in nine of the 10 babies treated in France.

SCID “is a disease that is 100 percent fatal without bone marrow transplants,” Woo said. “If [curing nine or 10 cases] isn’t proof that gene therapy is working, I don’t know what is.” Woo is chairman of the department of gene and cell medicine at The Mount Sinai School of Medicine in Manhattan and past president of the American Society for Gene Therapy.

“Poised for real success”

The arcane art of gene therapy has been making quiet strides that appear to mark medical history – to the point that researchers say once-untouchable diseases are on the eve of becoming curable.

“The field is now poised for real success,” said geneticist David Curiel, head of a large gene therapy research team at the University of Alabama, Birmingham. Curiel himself is seeking approval from the U.S. Food and Drug Administration to begin clinical trials of a virus engineered to infect and kill cancer cells, leaving the patient’s normal cells unscathed. The team’s first target will be deadly brain tumors.

“The state of gene therapy is good,” said Woo, who also is a scientific adviser to the Alliance for Cancer Gene Therapy, a private foundation supporting such research. “It has taken a long time because, for the past five years, investigators have hunkered down and refocused on the science” after the problems developed.

Fundamentally, the goal of gene therapy research is to find safe treatments for some extraordinarily difficult diseases by correcting or replacing the mutant genes that cause them. There are more than 4,000 known genetic diseases and, though most are rare, a few are not and include such disorders as cystic fibrosis, muscular dystrophy, hemophilia, Tay-Sachs disease and sickle cell anemia.

Even with recent successes, it is not likely that gene therapy will have an immediate role in treating the major health problems – most cancers and heart disease – without many years of research, experimentation and clinical trials. Nevertheless, more than half of the proposals before the FDA are aimed at various cancers.

Progress on several diseases

As gene therapy experiments have resumed, researchers cite encouraging results. Among them:

A treatment for difficult cancers of the head and neck. It uses a virus to insert a corrective gene, called p53, into cancer cells to halt uncontrolled tumor growth. China recently approved the treatment as a front-line weapon against such head and neck tumors. A Texas company, Introgen, has the same treatment in late stage clinical trials in this country.

Experiments in Philadelphia are showing that gene therapy may cure a rare form of congenital blindness that strikes infants. Work with dogs with a similar disease has yielded a 100 percent cure rate – garnering a “Wow!” from Woo. About a dozen dogs have been treated so far, he said, and “when this trial goes forward” in infants, “it will mean for a blind child, ‘I can now see the face of my mother.'” He said the dogs had no detectable side effects from the treatments, done by molecular biologist Jean Bennett at the Scheie Eye Institute’s F.M. Kirby Center for Molecular Ophthalmology, affiliated with the University of Pennsylvania.

Attempts to treat hemophilia by implanting healthy genes that make blood-clotting factors succeeded, but only briefly. Hematologist Katherine High at Children’s Hospital in Philadelphia says she is making progress toward understanding why.

A research team in Finland has doubled the expected survival time in some patients, from a matter of months to more than a year, with an aggressive form of brain cancer, glioblastoma. An enzyme-making gene is delivered into cancer cells, where it produces an enzyme called tyrosine kinase, making the cell vulnerable to a virus-killing drug.

Research in mice supports the possibility of getting new genes into most of the muscles of the body, necessary in treating muscular dystrophy, said Dr. Michael Blaese, research director at the Institute for Inherited Disease Research, a private charitable research foundation in Newtown, Pa.

Four more infants with SCID have been treated successfully in the United Kingdom, scientists have reported. Blaese, who was involved in that first authorized gene therapy experiment in 1990, done by the National Institutes of Health in Bethesda, Md., said because so little was understood then, the procedure was limited to the severely ill. “That’s why we started where we did, with SCID and brain tumors.”

From mistakes, lessons

As gene therapy research accelerates, scientists say more safeguards have been developed – and they have a better understanding of what went wrong, starting in 1999.

That’s when 18-year-old Jesse Gelsinger died after receiving gene therapy from University of Pennsylvania scientists. Experts identified two factors: He apparently got too large a dose of the adenovirus that delivered the gene therapy, and no specialist was on hand to respond to a sudden immune emergency.

In the cases in which leukemia developed, experts say the virus that ferried the genes mistakenly inserted them into a so-called oncogene, turning it on and, consequently, causing cancer. The experience confirmed the fear that the “disarmed” viruses could be dangerous.

Biologists had initially focused on using viruses as shuttles because they naturally invade living cells and deliver genes into a cell’s nucleus. Led by scientists such as Richard Mulligan, now at Children’s Hospital in Boston, researchers learned to erase a virus’ disease-causing genes.

But some of the viruses occasionally touch off immune reactions – some because they are grown in mouse cells afloat in calf serum, where they pick up chemical hints of mouse and cow, leading the patient’s immune system to attack materials that seemed to be foreign.

Creating a gene shuttle

So scientists began to pursue other possible “vectors.” At the leading edge of the science, chemist Robert Langer and colleagues at the Massachusetts Institute of Technology are testing one new approach: plastic.

That team has developed ways to manipulate the structure and other properties of various plastics, enabling tiny collections of plastic molecules to carry medicines directly to the tissues where they’re needed.

Using such a shuttle, they delivered a gene that makes diphtheria toxin directly into human prostate cancer cells growing in mice. It “suppressed tumor growth and even caused 40 percent of the tumors to regress in size,” Langer and his team reported.

The next chapter in gene therapy will be determined by clinical trials now awaiting the FDA’s go-ahead. For now, the Ohio girls who got the first treatment still get injections of a drug called PEG-ADA to help maintain their immune status, according to Blaese.

The younger one, Ashanti, is a freshman at Ohio State University, he said, looking toward a career in music. The other, Cindy, is due to graduate from Kent State University this year.