The results of a gene therapy trial on two children with Canavan disease, a rare, fatal, inherited metabolic brain disorder, show the transfer of a therapeutic gene can be successfully and safely introduced into the brain of young patients, with some positive effects. Researchers at Jefferson Medical College, who led the 1996 trial in New Zealand - a prelude to a larger study at Jefferson in 1998 and 1999 of 14 such patients - say the report bodes well for future use of gene therapy for brain diseases.
Canavan disease is a neurological disorder characterized by degeneration of the brain. It primarily affects children of Eastern European or Ashkenazi Jewish background. It is one of a group of genetic disorders called leukodystrophies that affect the growth of the myelin sheath of the nerve fibers in the brain. The myelin sheath is the fatty covering surrounding the nerve cells that acts as an insulator. The disease is caused by a genetic flaw in which an enzyme fails to be produced. Symptoms of Canavan disease, which appear in early infancy and progress quickly, may include mental retardation, loss or inability to acquire motor skills, difficulty feeding, loss of muscle tone, poor head control, and an abnormally enlarged head. Death comes within the first decade of life.
"This report presents the first gene transfer on two patients affected by a neurological disease," says Matthew During, M.D., professor of medicine at Jefferson Medical College and director of the CNS Gene Therapy Center at Thomas Jefferson University in Philadelphia.
Drs. During, Leone and their co-workers report the details of the trial in July in the Annals of Neurology. An editorial accompanies the report.
Canavan is caused by a defect in aspartocylase, or ASPA, an enzyme, which causes an over-production of a toxic compound in the brain, N-acetyl-aspartate (NAA).
"After the gene transfer, the patients had decreased NAA concentration in the brain followed by increased myelin as measured by MRI analysis as well as neurological improvements. Overall, we think it was an encouraging result for a preliminary gene transfer trial," says Paola Leone, Ph.D., assistant professor of neurosurgery at Jefferson Medical College and associate director of the CNS Gene Therapy Center.
Though the disease affects the children from birth, diagnosis takes some time. The children in the study received the gene transfer at ages 19 and 24 months, respectively.
"In an ideal condition, it would be better to perform the procedure as soon as the patients are diagnosed," Dr. During explains. "This result shows that gene transfer can be used to introduce a therapeutic gene in the brain that can modify the brain biochemistry. These children showed relatively small improvements, but small gains are large for those severely handicapped."
The researchers developed a gene delivery system based on liposomes and polymers, rather than viruses, to deliver the genetic information for the enzyme into the brain. They inserted the gene into the brain ventricles. The researchers found a slight decrease of NAA in one patient and a transient decrease in the other, an indirect indication that the gene reached its mark and was functioning.
"We saw the earliest changes in the myelin sheath surrounding the nerves at 12 months post-gene transfer," says Dr. Leone. "We were a little surprised because we thought the children were too old to show significant myelin increase detectable by MRI analysis and we also knew that the gene transfer using liposomes delivered in the ventricles was safe but not very efficient."
Dr. During explains that Canavan is a good disease model for gene therapy. It is caused by a single gene defect and the damage is restricted to the brain. "If the expression of the enzyme is normalized, the brain biochemistry can be normalized as well," he says. In addition, the biochemical imbalance can be measured non-invasively. An animal model has only recently been developed.
Dr. During recalls that in 1996, "No one realized that gene therapy could move into CNS diseases. Most gene therapies focused on cancer, cystic fibrosis, and more common genetic diseases," he says.
Dr. During and his collaborators hope to begin a new trial later this year or early next year using a new, improved, safe and effective system for the delivery of a therapeutic gene in Canavan disease. The protocol currently is under review by the federal Food and Drug Administration.
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Journal
Annals of Neurology