Gene therapy cocktail shows promise in long-term clinical trial for rare fatal brain disorder

Results of a clinical trial that began in 2001 show that a gene therapy cocktail conveyed into the brain by a molecular special delivery vehicle may help extend the lives of children with Canavan disease, a rare and fatal neurodegenerative disorder.

A report of the trial appears in the Dec. 19, 2012 online edition of the journal Science Translational Medicine.

The form of gene therapy was created and developed at the University of North Carolina School of Medicine. The work was spearheaded by R. Jude Samulski, PhD, a study senior author, professor of pharmacology and director of UNC's Gene Therapy Center. The treatment uses a virus (adeno-associated virus, or AAV) as a "viral vector" meticulously tailored to enter the brain and safely switch good genes for bad.

"This was the first AAV-based gene therapy produced by a U.S. academic institution to be approved for neurological use by the FDA," Samulski said. "It's also the first vector produced by the university's Gene Therapy Center Vector Core facility to go into patients."

Children with Canavan disease have mutations in the ASPA gene that normally codes for an enzyme that helps the brain degrade N-acetyl-aspartate (NAA). The unregulated buildup of NAA is toxic to the brain's gray matter, the protective myelin sheath surrounding nerve cells. As the myelin deteriorates and neurons becoming unable to communicate, the child's head size increases (macrocephaly), there are movement problems such as an inability to crawl, seizures occur, vision becomes impaired, and the children often die within three years of age. Fewer than 1,000 children in the U.S. have the disorder.

Samulski arrived at UNC in 1993 to establish the UNC Gene Therapy Center and has long pioneered methodologies for using viruses to deliver genes effectively and safely to various targets in the body, including the brain, lungs, liver, heart, and muscle. As a graduate student at the University of Florida in the early 1980s, his thesis project was understanding and developing AAV as a vector for delivering therapeutic genes which has help launch this new field of molecular medicine. This work eventually led to development of AAV type 2, which has been used for gene therapy vector trials in cystic fibrosis, hemophilia, Parkinson's diseases, retinal disorders, and in several other settings, including the first gene therapy clinical trial for muscular dystrophy in the U.S developed by Dr. Samulski and his first graduate student, Dr. Xiao Xiao, professor in the UNC Eshelman School of Pharmacy.

What is Canavan disease?

Canavan disease is an inherited disorder that causes progressive damage to nerve cells in the brain. This disease is one of a group of genetic disorders called leukodystrophies. Leukodystrophies are characterized by degeneration of myelin, which is the fatty covering that insulates nerve fibers.

The signs and symptoms of this disease usually begin in early infancy; however, the course of the condition can be quite variable. Infants with Canavan disease typically appear normal for the first few months of life. By age 3 to 5 months, affected infants begin having problems with development, including a delay in motor skills such as turning over, controlling head movement, and sitting without support. These infants typically also have weak muscle tone (hypotonia), unusually large head size (macrocephaly), abnormal posture, and intellectual disability. Feeding and swallowing difficulties, seizures, and sleep disturbances may also develop.