Public Release: 

With government nod, gene therapy pioneered at UNC is given to children with rare disorder

University of North Carolina Health Care

CHAPEL HILL -- A form of gene therapy created and produced at the University of North Carolina at Chapel Hill and approved by the U.S. Food and Drug Administration has been given to children with a rare, inherited neurological disorder.

This work involved collaboration with investigators at the Robert Wood Johnson Medical School, of the University of Medicine and Dentistry of New Jersey, and was led by Dr. Paola Leone and a group of 16 investigators and surgeons.

The children have Canavan disease, characterized by spongy degeneration of the brain's white matter. The disease affects the growth of the fatty myelin sheath insulating nerve fibers.

Canavan disease symptoms appear in early infancy and progress rapidly. These may include mental retardation, loss of previously acquired motor skills, feeding difficulties, abnormal muscle tone (floppiness or stiffness), poor head control and megalocephaly (abnormally enlarged head). Paralysis, blindness or hearing loss also may occur.

There is no cure for Canavan disease or a standard course of treatment other than symptomatic and supportive. Prognosis is poor; victims usually die before age 10.

"Children with Canavan disease have a mutation in one of their genes, causing a deficiency of an enzyme responsible for removing cellular waste," said Dr. R. Jude Samulski, professor of pharmacology at UNC's School of Medicine and director of the Gene Therapy Center. "In this disease, waste product builds up, causing brain cells to die."

Absolutely nothing can be done to prevent disease progression, said Samulski, which is why the objective was to place a gene into the brain that would express the missing enzyme.

The therapy received by the children uses a genetically altered adeno-associated virus, or AAV, to deliver genes into the body. Samulski, a pioneer in AAV research, said he chose to study and develop altered AAV for several reasons, including its potential for fewer toxic effects than that of many other viruses studied for use in gene therapy.

Moreover, a gene delivered via AAV remains active in cells for months or even years.

This is the first time the FDA has approved the clinical use of an AAV vector product for gene therapy produced by a U.S. academic institution.

The children who received the gene therapy are between ages 4 and 6, and the procedure was conducted recently at the Robert Wood Johnson Medical School. Surgeons drilled a series of six holes in the skull through which the virus and its gene payload was infused directly into various brain sites.

Recovery from the surgery is rapid and does not require lengthy hospitalization, Samulski said. The children return home within a few days.

When infused into the brain, AAV begins to "infect" neuronal cells via molecular doorways on the surface. "The AAV vector then begins delivering the gene, and that genetic information gets 'read' as part of the normal genes in the cell," Samulski said.

"We're essentially replacing the function of the mutated gene. That gene is still at its original chromosome location in the nucleus. What we're introducing is not in the chromosome but attached to the nucleus of the cell. So we're delivering extra-chromosomal DNA that has all the 'start' and 'stop' signatures and other information the cell needs to make the appropriate protein; in this case, the missing enzyme." While a cure is highly unlikely, researchers hope disease progression can be slowed, if not halted. Two weeks following surgery, the children are given a battery of tests, including nuclear magnetic resonance imaging, or NMR. The first NMR study will mainly look for safety endpoints, including tissue damage after surgery.

"At three months onward NMR imaging and NMR spectroscopy studies will provide information regarding elevated levels of an enzyme substrate associated with cellular waste product and brain myelination patterns," Samulski said. "Decline of the substrate indicates that the virus is working and the gene is expressing and starting to break down the waste product," Samulski said.

More subjective signs of progress over time include weight gain. In addition, on a cognitive level, parents may notice an increased ability to respond to demands.

"In this clinical trial, for these children, we're hoping to halt further deterioration. It's not likely we can regenerate new brain tissue," Samulski said. He added that any indication of progress would provide increased impetus to treating normal infants shown by screening tests to likely develop the disease.

Molecular studies in Samulski's laboratory using animal models are aimed at improving vector systems for delivering gene therapy. One goal is to achieve global distribution of the virus to brain tissue.

"We're optimistic that our next generation of vectors will safely bring to patients something well beyond marginal improvement," he said. "One can't underestimate the importance of understanding the basic science first before moving into the clinical setting."

Key to gene therapy vector research at UNC is the Human Applications Laboratory, or HAL. Located in the General Clinical Research Center at UNC Hospitals, this 1,400-square-foot facility was designed for production of various biological reagents, including viral vectors, that may be required for phase I (safety and efficacy) clinical trials.

The facility meets FDA requirements for germ-free processing. Viral vectors and their components are generated at high purity and concentration levels.


UNC School of Medicine

Note: Contact Samulski at 919-962-3285 or
School of Medicine contact: Les Lang, 919-843-9687 or

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