Gene therapy cocktail shows promise for rare fatal brain disorder

A CLINICAL trial that began in 2001 has shown results 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.

In this Canavan disease phase 1/2 safety study, 13 children were treated at the Cell and Gene Therapy Center at the University of Medicine and Dentistry of New Jersey (UMDNJ) in Stratford, N.J. Principal Investigator and first author of the study is Paola Leone, PhD, associate professor of cell biology at UMDNJ. The children were treated in 2001, 2003 and 2005, corresponding to AAV vector production runs. Their ages at the time of treatment ranged from four to 83 months.

Working with Samulski’s UNC lab colleagues, Leone’s neurosurgical team used MRI imaging to guide them to the proper location and depth in the lateral ventricle of the brain for inserting six very thin catheters via small holes drilled in the skull.

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