A genetic intervention for children with rare disease

Yale investigators are evaluating a potential therapy for Canavan disease, a rare neurological disorder in children that is usually fatal. Eight children have been cared for at Yale this year as part of a clinical trial to test the safety of the treatment, which uses gene therapy techniques to replace a critical enzyme in the brain.

Children with Canavan disease cannot hold their heads up, have trouble eating and may suffer seizures. Few live past the age of 10. The genetic disease strikes children of all ethnic groups, occurring most frequently among Ashkenazi Jews.

According to Margretta R. Seashore, M.D., the principal investigator in the study, the current phase of the trial will assess its safety. Yale's Human Investigation Committee and its Biosafety Committee are also monitoring the study. A ninth child is undergoing the therapy at Thomas Jefferson University Hospital in Philadelphia. If the procedure proves safe, the FDA may allow researchers to add six more children to the trial.

Although the Phase I trial is focused on the safety of the procedure, researchers are watching for signs of improvement in the children. “It's really too early to know whether we've got some encouraging signs of therapeutic effect,” said Maurice J. Mahoney, M.D., a member of the Human Investigation Committee. The only reported side effect among the children has been a high fever that is typical of gene therapies and easily treated, said Dr. Seashore, professor of genetics and pediatrics.

Treatment starts with the insertion of a 2-inch-wide rubber reservoir under the scalp. A slender catheter carries the gene to synthesize aspartoacylase (ASPA), an enzyme missing in Canavan disease, into the ventricle of the brain. Although researchers are still trying to understand the exact mechanism, without ASPA a chemical called N-acetylaspartic acid builds up and myelin, the “white matter” that protects nerves and allows messages to be transmitted to and from the brain, becomes deficient. Researchers hope their therapy will stimulate the brain to produce ASPA and slow down or reverse the progress of the disease.

Parents recognize that the therapy is experimental and may not help their children. “There will either be a benefit or there will be nothing,” said Howard Gluckman of Johannesburg, South Africa, who calls his son, Asher, 9, the granddaddy of the group. The youngest child in the group is 19 months. “At least they're not in danger from the procedure.”

“It's a first step,” said Matthew During, M.D., a visiting professor at the medical school who conducted previous gene therapy trials in New Zealand. “It gives us a level of comfort and confidence in moving forward.”