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Source: The Ottawa Citizen, Wednesday, January 23, 2002
Discovery offers hope to children with fatal genetic disease
Ottawa Health Research Institute finds way to replace missing gene in preliminary tests
By Tom Spears
Three Ottawa researchers have taken a first step toward curing children born with an always-fatal genetic disease that makes their muscles and lungs shut down.
About one baby in 6,000 is born with spinal muscular atrophy, caused by a missing gene. Without the protein produced by that gene, motor neurons can't survive, and a baby starts to weaken about six months after birth. The baby's muscles get floppy and the baby starts to have trouble breathing.
With the most severe form of the disease, he or she will die of paralysis and respiratory failure before two years of age. Those with milder forms will live longer, but still die from it. The gene was identified about five years ago, but there is still no treatment other than trying to clear up lung infections, and providing children with braces and wheelchairs to prop up their bodies.
Now, molecular biologists at the Ottawa Health Research Institute have implanted a new version of the gene that's missing in these children in such a way that it appears to "switch on" and do the work of a normal healthy gene.
It's not a cure yet. So far, the gene replacement has only worked in single cells in a test tube. But as tests in live mice are about to begin, the early success is a promising step forward toward eventual gene therapy in children.
When the gene is missing, cells fail to produce enough of a protein called survival motor neuron, or SMN. But there's one piece of luck: Humans have an extra copy of the gene. Even children who are missing the main gene produce a little SMN -- not enough to survive, but enough that their bodies will recognize it and won't mount an immune response if they can somehow start making more.
The Ottawa research group seized on that, and has found a potential way to replace the missing gene so that it will manufacture more of the vital protein in nerve cells. Christine DiDonato, Robin Parks and Rashmi Kothary use a well-known technique, loading the gene that makes SMN into a harmless virus, and making the virus infect cells, taking the gene along for the ride. If it works, they reasoned, the new gene should join the rest of a patient's gene set and go to work.
So far, the tests have taken place in individual cells from patients with spinal muscular atrophy. This means that the researchers have to look for the types of reaction they would expect inside a single cell if the gene is working.
They've found them. Children with spinal muscular atrophy lack tiny, dot-shaped structures in the cell called "gems," which are rich in SMN protein. But Ms. DiDonato says that when her group infected cells with the replacement gene, "we were able to increase intracellular levels of SMN" and caused the missing "gems" to appear. As well, she said, "the protein we made from our viral vector was able to interact with the other intracellular normal partners that SMN would normally interact with.
"That's a very important first step. Now we're moving on into the next step, which is to go on into animal models," where the therapy must be proven safe and effective before it can be tested in human children.
A group representing families whose children have the disease says it's excited by the news. "This progress moves us closer to the day when we can say there is an effective treatment for SMA available," said Darren Bray, president of Families of SMA Canada. The group helped fund the Ottawa Health Research Institute research.
Spinal muscular atrophy is the most common genetic cause of death in Canadian infants. Results of the study appear in this week's issue of a medical journal called Human Gene Therapy.
(Reprinted with permission from The Ottawa Citizen)