Jefferson Researchers Use Gene Therapy To Treat Rare, Inherited Brain Disease

Researchers at Jefferson Medical College are for the first time attempting to use gene therapy to treat Canavan disease, a rare, fatal metabolic brain disorder.

A team of neurosurgeons are treating a four-year-old Illinois girl at Thomas Jefferson University Hospital, Thomas Jefferson University, Philadelphia. The group includes Andrew Freese, M.D., Ph.D., associate professor of neurosurgery and director of neurosurgery research, Matthew During, M.D., professor of neurosurgery, Paola Leone, Ph.D., adjunct assistant professor of neurosurgery, and Giancarlo Barolat, M.D., professor of neurosurgery, as well as their colleagues there and at Yale University.

Canavan disease is an inherited neurological disorder characterized by spongy 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. The disease is incurable, resulting in the over-production of a toxic compound in the brain, N-acetyl-aspartate (NAA). Death usually occurs between the ages of 5 and 7.

Symptoms of Canavan disease, which appear in early infancy and progress quickly, may include mental retardation, loss of previously acquired motor skills, difficulty feeding, abnormal muscle tone, poor head control, and an abnormally enlarged head. As time progresses, sufferers also become paralyzed, blind, and lose hearing and their interaction with the outside world.

"Children fail to meet normal developmental milestones," Dr. Freese explains. "Within a few years, they cannot feed themselves, walk, or see well." Dr. Freese says that the disease is similar to Tay-Sachs disease in that both are metabolic disorders causing the buildup of toxic compounds that affect normal brain development.

According to Dr. Freese, three years ago, his colleagues at Yale were contacted by Canavan families for their expertise in gene therapy to see about the possibility of developing a therapy for the disease. Drs. During, Leone and Freese 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 have shown that the system works in the lab and in animals. They then showed in preliminary studies in New Zealand that the Canavan gene could effectively be delivered into the brains of two children with Canavan disease, based on evidence of nerve myelination and on behavioral studies. They have gained federal Food and Drug Administration approval, Dr. Freese notes, to expand the work into a larger Phase 1 clinical trial.

To date, the Jefferson team plans to treat four Canavan disease children.

The therapy will consist of a ventricular catheter implanted under the scalp, allowing access to the brain's ventricles and cerebrospinal fluid, and to allow possible additional treatment. The Jefferson researchers are collaborating with specialists at Children's Hospital of Philadelphia to monitor myelin and enzyme levels using magnetic resonance spectroscopy and magnetic resonance imaging. "We'll also look at behavioral aspects of the children--a whole battery of tests before and after gene therapy," Dr. Freese points out.

"We anticipate expanding our gene therapy approach to other inherited metabolic disorders, such as Krabbe disease," he notes, together with David Wenger, Ph.D., professor of medicine at Jefferson Medical College, who leads the Lysosomal Disease Testing Laboratory. "We hope to set up a clinical trial for that within the next year as well."

He cautions that few patients have been treated this way as yet.

"They [results from this trial] may give us some information about the possibility of treating other neurological disorders, such as other inherited diseases, and Parkinson's disease, stroke and epilepsy," he concludes.