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Gene Therapy Shows Promise for Brain Disorder - cyrano - 05-14-2008 07:41 AM

By Jocelyn Kaiser
ScienceNOW Daily News

A daring attempt to use gene therapy to treat a rare, devastating disorder that destroys the brains of children has shown signs of slowing the disease's progression, according to a new paper. However, some experts aren't convinced that the treatment, which involved dripping a virus into young patients' brains, actually worked.
The children all have late infantile neuronal ceroid lipofuscinosis (LINCL), a form of the neurodegenerative disorder Batten disease. They were born without a working copy of CLN2, a gene whose protein helps lysosomes--the cell's garbage-disposing structures--break down a waste product called lipofuscin. As a result, lipofuscin builds up and eventually destroy neurons, causing the brain to shrink. Children with LINCL seem normal at birth but by age 2 to 4 show signs of developmental problems and often have seizures. Eventually blind and confined to a wheelchair, they usually die by 8 to 12 years of age.

A few years ago, gene therapy researcher Ronald Crystal and colleagues at Weill Cornell Medical College in New York City successfully slowed LINCL in mice using gene therapy in the brain. To test the safety of the approach in humans, the team treated 10 LINCL patients ranging in age from 3 to 10 years, starting in 2004. After anesthetizing the children, the researchers drilled six 2-mm-wide holes in their skulls. They then dripped in a solution of a harmless virus that had been modified to carry a good copy of the CLN2 gene. Four children had an immune response, but it was mild. One patient developed seizures 2 weeks later and died 49 days after the surgery. However, she did not have brain inflammation, and Crystal says it was not clear whether her death had anything to do with the gene therapy.

Over the next 18 months, Crystal's team conducted neurological tests and magnetic resonance imaging (MRI) scans. Although the MRI scans suggested that the brains of treated children were shrinking less than they would have otherwise, the results were not statistically significant. On measures of motor function, language, and seizure frequency, however, the children appeared to deteriorate more slowly compared with untreated patients, dropping about two points less on a nine-point scale than controls. "This is suggestive [of efficacy] and encourages us to move on," says Crystal, whose team reports its results online today in Human Gene Therapy. The roughly $8 million study was funded by Nathan's Battle Foundation, which was started by the parents of two siblings with LINCL, both of whom were enrolled in the study.

Experts are viewing the results with caution. "This is potentially exciting, but it's also potentially not going to hold up," says neurologist Jonathan Mink of the University of Rochester Medical Center in New York state. The study's main flaw, says Jonathan Cooper, a neuroscientist at King's College London in the United Kingdom, is the untreated patients used for comparison. It is not clear how comparable these controls were in their disease stage with the treated patients, so it's hard to be sure that the treated patients did better than they would have otherwise.

Crystal hopes to improve on his team's results by using a different type of viral vector that worked much better in mice in his latest studies. He says the next trial could begin in a year.

Meanwhile, researchers have treated another inherited childhood brain disease called Canavan disease with gene therapy. The lead investigator on one of these trials, Paola Leone of the University of Medicine and Dentistry in Camden, New Jersey, says that her team is preparing a manuscript on its study of 13 patients. At meetings, she has reported "significant improvement" in certain measures of cognitive and motor function.