Genetic action shows results on rare brain disease in children
Children often die of complications from Canavan disease by age 3, and almost always by 10. But 10 of the 13 study participants have passed age 10, with three in their late teens.
None can walk or talk, but all can respond to their environment to some degree, and lab tests show that the degeneration of their brains has slowed or leveled off. Ordinarily, such patients become nonresponsive by 5 if they make it that far, researchers said.
The lead author of the study was Paola Leone, an associate professor of cell biology at the School of Osteopathic Medicine in Stratford.
Ten of the children were treated at Cooper University Hospital, the other three at Thomas Jefferson University Hospital, starting in 2001.
This study was among the first that received government approval to introduce therapeutic genes into the brain, by injecting a special deactivated type of virus that carries genetic instructions to replace the body's flawed version.
The trial's primary goal was to show that these adeno-associated viruses were safe. That paved the way for subsequent gene therapy trials for other brain diseases.
Gene therapy, after a slow start, has seen successes in recent years, including an experimental treatment for certain blood cancers at the University of Pennsylvania.
Nicholas Boulis, an associate professor of neurosurgery at Emory University School of Medicine, is looking at viruses similar to those in Leone's trial as treatments for Alzheimer's and Parkinson's. He said that without Leone's work, he could not do so.
"Now the handcuffs are off, because we know we can do this safely," he said.
The work with Alzheimer's and Parkinson's is slightly different. Boulis and his team are not seeking to replace a faulty gene, but to insert extra genes that will augment the brain's normal production of certain growth factors.
What happens next with Canavan is unclear. The study, published in the journal Science Translational Medicine, cost $3.2 million, much of it from the National Institutes of Health, the rest from various foundations and donors. At the moment, there is no money for a larger trial, Leone said. Drug companies do not often pursue drugs for such rare diseases if they have little chance of turning a profit.
Leone said no more than 150 children in the United States have Canavan.
Jordana Holovach, founder of Jacob's Cure, one of the groups that helped fund the research, said she was optimistic. The foundation, based in Rye, N.Y., raised a total of $1.8 million with two galas in 2011 and this year. It is shooting for $1 million at the next such event, in May, she said.
The foundation was named for her son Jacob, who will turn 17 in February and was a trial participant. The fact that the research had applications for Parkinson's and other more common diseases will help in persuading people of its wider importance, she said.
She said the injection of the gene-bearing viruses had given Jacob better motor control and vision. He also suffered fewer respiratory problems, which often plague children with Canavan.
"While it wasn't a cure, it was significant for him," she said.
The researchers had even greater hopes for the youngest patient, Shippensburg, Pa., resident Ariel Coover, who was injected in 2005 at 31/2 months of age.
Canavan is caused by a mutation in a gene that carries the recipe for an enzyme that breaks down an amino acid called NAA. In patients with such mutations, NAA builds up to toxic levels, eventually with disastrous effects for the white matter of the brain.
The hope was that since Ariel was treated so early, injected at six brain sites, the disease might have been largely prevented.
But Leone said researchers now know that the disease progression starts even earlier. For greater success, Leone said, she would inject patients sooner, with three times as many of the gene-bearing viruses, in 18 locations instead of six.
Ariel's mother, Peggy, said she was grateful for the care. The Coovers had an older daughter, Amber, who also had the disease and died at 7.
Ariel has now reached that age, and is much more alert and communicative than her sister. She can lift her arms and smile to indicate yes. To indicate no, she turns away. She can hit a switch to turn on a string of lights hooked up over her head, her mother said.
"I think it's really helped her," Coover said of the therapy. "They just need to do more research."
Besides the School of Osteopathic Medicine, several other institutions participated in the study, including Children's Hospital of Philadelphia, which did some of the follow-up tests.
If the researchers are able to pursue further study, the Coovers would welcome it not just for Ariel. They have a younger daughter, 2-year-old Kaydi, who also has been diagnosed with the disease.