CANAVAN DISEASE International efforts rely on gene therapy

Scientists have long sought a cure or effective treatment for the rare disorder.
MILWAUKEE -- Four-year-old Ashtyn Fellenz cannot sit up, raise her head or talk. And she "eats" only through a tube attached to her stomach. The Menomonee Falls, Wis., girl has a rare genetic brain disorder known as Canavan disease.
Ashtyn is one of only 21 participants from the United States, Europe and South America in an enterprising clinical trial where researchers pump genes into the brain in hopes of improving motor skills and brain function.
A floppy head and stiff limbs are trademarks of the disorder. Other symptoms include mental retardation, blindness, deafness and paralysis.
Disease results
With Canavan disease, a malfunctioning gene causes a buildup in the brain of a chemical called N-acetyl aspartate. The gene fails to produce a protein responsible for breaking this substance down into the building blocks of the brain's white matter.
Also called myelin, white matter is a fatty layer that coats nerves in the brain and spinal cord. It transmits nerve impulses from the brain to other cells in the body. In Canavan disease, the white matter becomes spongy and full of tiny fluid-filled holes.
Children with the disease usually die by age 4 but in rare cases could live into their 20s, according to the National Institute of Neurological Disorders and Stroke.
The clinical trial -- which began in April 2003 and will run through summer 2005 -- is testing how gene therapy can improve the odds for children with Canavan disease.
Seeking a cure
"This is a first step; the potential down the road for a cure is a real one," said Christopher Janson, principal investigator of gene therapy for Canavan disease at Cooper Hospital, a branch of the University of Medicine and Dentistry of New Jersey. Researchers from Robert Wood Johnson Medical School -- another branch of the same university -- and Children's Hospital of Pennsylvania are also part of the team. The group plans to extend its methods to treating more common neurodegenerative disorders such as Alzheimer's, Parkinson's and Tay-Sachs.
Eight years ago, in New Zealand, the same group performed the first gene therapy treatment of a genetic brain disorder on children with Canavan disease. This work ruffled some feathers within the gene-therapy field because the investigators tested the method on humans without first showing that it was effective in animals.
At the time, they delivered genes surgically, using a fat-based molecule to shuttle genes to the brain.
Gene therapy
These days, the team delivers genes using a different kind of brain surgery as well as a new vehicle -- an adeno-associated virus.
But some gene-therapy experts remain cautious because no researchers have successfully used that kind of delivery method in humans.
Adding to the uncertainty, in late May, California-based Avigen Inc. -- a company that develops gene-therapy products -- yanked its support from a hemophilia gene therapy trial that used this type of delivery to supply genes to the liver. Two of seven patients in the study -- conducted at Stanford University, Children's Hospital of Pennsylvania and University of Pittsburgh -- developed mild liver trouble. The researchers feared the toxicity might interfere with the treatment, said Mark Kay, one of the trial's scientific advisers based at Stanford. Test animals had not shown any liver damage.
"You can't always predict what will happen in humans even if you have the best animal studies," Kay said.
Method is different
The Canavan disease researchers are unfazed. Immune responses to a virus used in the liver do not necessarily forecast what will happen when the virus is used in the brain. Indeed, in the Canavan disease trial, tests of blood serum and spinal fluid show that there is little immune response to the virus or to the gene's protein products, Janson said.
Furthermore, the difference in gene delivery method between the two trials will also affect the results, said Paola Leone, co-principal investigator of the Canavan disease trial. In the hemophilia trial, the virus was administered to an artery and transported through the bloodstream to the liver. In the Canavan disease trial, the virus was injected directly into the brain.
"If they demonstrate that it is effective in Canavan, it would be a remarkable result," said Roscoe Brady, chief of the developmental and metabolic neurology branch of the National Institute of Neurological Disorders and Stroke.
Since her gene therapy treatment one year ago, Ashtyn can now move her head from side to side and even lift her arms and legs in ways she was unable to do before. And her facial expressions have a brightness that wasn't there before, said her nurse, Jacalyn Anderson.
Ashtyn has come a long way. "She used to be just a rag doll," said Ashtyn's mother, Arlo Clark-Fellenz.
The simple act of swallowing is a chore for children who have Canavan disease, a disorder that affects mainly Ashkenazi Jews and people of Saudi Arabian descent. Neither of Ashtyn's parents has a known Jewish or Saudi Arabian heritage. Both parents must carry the culprit gene mutation for offspring to have the disease. There is then a 1-in-4 chance a child will be born with the disease. A simple prenatal blood test can reveal if a child is affected. Parents can be screened to see whether they are carriers of the defective gene that causes the disease.

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