Amy and Derick Martin are waiting for a new type of gene therapy that might save their lives.
Amy Martin, 8, wants other kids to stop staring at her yellow eyes. Her mom explains that those kids don't understand that Amy and her brother Derick, 10, have an unusual disease. Amy and Derick would like that disease to take a hike. They long to look like other kids and to sleep like them, too--in pajamas, under warm blankets, with the lights off--but that would interfere with their therapy.
Amy and Derick suffer from a rare genetic, or inherited, disease marked by, among other things, jaundice--a yellowing of the skin and the whites of the eyes. Current therapies have helped children like Amy and Derick survive through their teens and 20s, but rarely past age 30.
That could change soon. Researchers are hoping to cure Amy and Derick's affliction and thousands of other genetic diseases by using a new type of therapy, called gene repair.
The disease that Amy and Derick have is Crigler-Najjar syndrome (KRIG-ler NAJ-ahr). Like thousands of other genetic diseases, Crigler-Najjar is caused by a faulty gene. Genes are tiny bits of biological material that control the workings of human cells. Genes determine what we look like and how our bodies function.
The normal version of the gene that's faulty in Amy and Derick's bodies controls the production of an important liver enzyme, a kind of protein that speeds up chemical reactions in the body. That enzyme is involved in ridding the body of bilirubin (bil-e-ROO-bin), a substance that's produced when the body breaks down worn-out red blood cells.
Everyone produces bilirubin, but in people with Crigler-Najjar, the enzyme that acts on bilirubin is in short supply or is missing altogether. In either case, bilirubin remains in the blood, causing jaundice, and can rise to life-threatening levels.
"In a matter of hours, people with the disease can go from being normal to being wheelchair-bound," said Holmes Morton, Amy and Derick's physician.
Morton keeps bilirubin levels stable with phototherapy--exposure to high-intensity blue light that penetrates the skin and converts bilirubin into a nontoxic form that's excreted in the urine. Without phototherapy, the excess bilirubin might slip inside the brain, where it can cause deafness, seizures, uncontrollable jerky movements, difficulty swallowing, vision problems, and death.
Ever since they were newborns, Amy and Derick have slept under blue lights for eight to 12 hours a night. Unfortunately, those lights won't always be effective. As children grow bigger, the penetrating power of the lights dwindles. "I just don't like to think about what can happen," said Amy and Derick's mom, Katie Martin. "We have to keep on our toes all the time."
When phototherapy begins to fail, Amy and Derick may need liver transplants. A healthy new liver would produce the enzyme that acts on bilirubin. Still, a transplant involves risks and complications. To live with a new liver, Amy and Derick would have to take a host of immunosuppressive drugs, which stop the body's natural rejection of foreign substances, including transplanted organs.
"As parents of Crigler kids often say, liver transplants are a matter of exchanging one big problem for another," said Morton. "Liver transplants are complex, dangerous. and risky, just like Crigler's disease. That's why we want to do gene repair."
Gene repair is a new type of gene therapy. For ten years, researchers have tried to treat genetic diseases by replacing the faulty genes that cause them. Unfortunately, those attempts have produced only limited success in a handful of people. Researchers haven't been able to find the right vectors, or biological vehicles, to transport healthy genes into the human body. (See "Gene Therapy Turns 10.")
Gene repair, also known as chimeraplasty, is an attempt to fix, rather than replace, flawed genes. The technique has shown great promise in the laboratory and is boosting some scientists' hopes that it could eventually cure millions of people with genetic diseases. "Chimeraplasty is the new generation of gene therapy," said Michael Blaese, the researcher who helped pioneer the world's first human gene therapy ten years ago.
Blaese, 61, recently quit what he called "the best job in the world," as chief of the clinical gene-therapy program at the National Institutes of Health (NIH). He then joined forces with ValiGen, a small biotechnology company experimenting with gene repair. Blaese decided to take a gamble on the new technique because it might make a lasting difference in the lives of millions of people who have genetic illnesses.
Crigler-Najjar doesn't affect millions, but it does affect a cluster of children who live in Pennsylvania, where ValiGen is based. Two years ago, Blaese visited Morton's small Pennsylvania clinic to talk about using gene repair to treat Crigler kids. The doctors scheduled a meeting with a group of parents whose children had the disease.
Derick and Amy's mom and dad were among those parents. They listened intently as Blaese warned them that the therapy was still in its experimental phase, but that the laboratory studies appeared promising. He showed them a photograph of two pairs of baby rats. One pair was yellow because the rats were afflicted with a rat version of Crigler-Najjar syndrome. The other pair used to be yellow but appeared a healthy pink because they had received gene repair.
The pink rats had been treated with a medicine containing bits of healthy genetic material. That material prompted a natural repair system in the rats' cells to fix the faulty gene. After that, the rats' livers began to make the enzyme that acts on bilirubin.