Gene-swap therapy eases rare brain disease

UNC-CHAPEL HILL (US) — A new therapy that uses a virus to switch genes in the brain may help extend the lives of children with a rare and fatal neurodegenerative disorder.

The results of the clinical trial, which began in 2001, show that the gene therapy cocktail conveyed into the brain by a molecular special delivery vehicle holds promise for children with Canavan disease.


As reported in Science Translational Medicine, 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 US academic institution to be approved for neurological use by the FDA,” says R. Jude Samulski, professor of pharmacology and director of the University of North Carolina Gene Therapy Center.

“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 become unable to communicate, the child’s head size increases (macrocephaly), there are problems with movement, such as an inability to crawl, seizures occur, vision becomes impaired, and the children often die by age three. Fewer than 1,000 children in the US have the disorder.

The current 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. The children were treated in 2001, 2003, and 2005, corresponding to AAV vector production runs. Their ages 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.

The team then pumped in a solution carrying the vector package containing the replacement ASPA gene. This amounted to about 900 billion genomic particles of replacement gene held by the AAV vector—roughly the size of a quarter—that were pumped into each of the catheter sites. The catheters were then removed.

Following the treatments, the patients went home with their families and were tracked with behavioral tasks and brain imaging studies. The investigators found that the gene therapy was safe and has led to a decrease in NAA in the brain, together with decreased seizure frequency and “clinical stabilization,” the greatest observed in youngest patients, those treated before 2 years of age. These include improvements in attention, sleep, and greater degree of movement improvements when lying down and rolling.

“As the trial continued, the FDA let us go to younger and younger patients,” Samulski reports. “We were successful in being able to treat a 3-months-old infant who was diagnosed in utero … and that child is alive today and is the youngest person who has ever been treated with gene therapy.”

Samulski views the study a definite success from the safety perspective. “The genetic information put into the brains of individuals has not caused adverse effects, toxicity, or cancer. It also has great potential efficacy for treating other degenerative neurological disorders, including Parkinson’s and Alzheimer’s diseases.”

The National Institute of Neurological Disorders and Stroke (NINDS), Canavan Research Foundation, Jacob’s Cure Foundation, and the National Endowment for Alzheimer’s Research funded the research.

Source: UNC-Chapel Hill