The scientist who discovered "Sly Syndrome" nearly four decades ago and a team of colleagues at Saint Louis University are a step closer to finding an approach to treat the rare genetic disease. Sly Syndrome causes bone defects, mental retardation, vision and hearing problems, heart disease and premature death.
They found that a potentially life-saving enzyme can be induced to cross the blood-brain barrier, a structure which protects the brain from foreign substances, if it is given with the hormone epinephrine.
Ever since William S. Sly, M.D., chairman of the department of biochemistry and molecular biology at Saint Louis University, discovered the rare genetic disease in 1969, he and his colleagues have conducted research to learn more about how to treat it.
He says their recent findings have significance beyond treating the extremely rare disease that bears his name.
"There are at most 100 living cases of Sly Syndrome. Nonetheless, this disease is a model for all the diseases in this group, some of which are much more common," Sly says.
"Lysosomal storage diseases affect 1 in 7,000 live births, and 90 percent of those with the diseases have brain involvement. What we find with Sly Syndrome has some importance for all those diseases as well. It is potentially a big finding and an important first step."
The discovery potentially points to a new way to get big molecules, such as certain medications, across the blood-brain barrier. It is reported in the Proceedings of the National Academy of Sciences online early edition the week of July 16.
SLU researchers found that the right amount of epinephrine probably works by stimulating transport by vesicles -- blister-like wrappers that carry substances across the blood-brain barrier - so that the enzyme missing in patients who have Sly Syndrome can get into the brain.
Those who have Sly Syndrome lack the enzyme called beta-glucuronidase. Without this enzyme, protein-sugar molecules accumulate in the brain and other organs in the body. By replacing the missing enzyme, doctors believe they can treat the genetic disease.
The problem, though, was slipping the enzyme past the blood-brain barrier to where it needs to do its work.
"This is a disease that is simply made for testing drug delivery vehicles. If you can get the enzyme into the brain, the vehicle that delivered it could work to deliver other chemicals, too," says William A. Banks, M.D., professor of geriatrics and pharmacological and physiological sciences at Saint Louis University, and a leading researcher on the blood-brain barrier.
Sly Syndrome, which occurs in fewer than one in 100,000 births, is a progressive disorder that ranges in severity from mild to deadly. It is among a group of genetic diseases call mucopolysaccharidoses.
"Some children who have this group of diseases are doomed to an early death because they don't make a certain enzyme," Banks says.
Enzyme replacement therapy -- or putting the missing enzyme into the bodies of those who have Sly Syndrome -- holds promise in treating the physical problems of the disease.
"In the case of Sly Syndrome, the missing enzyme is more than 1,000 larger than a sugar molecule and so huge it can't get across the blood-brain barrier, which prevents it from reaching the brain."
Scientists used a mouse model to figure out how to get the enzyme into the brain. They knew that injections of the missing enzyme into the brains of baby mice reached their target, but similar injections into mature mice did not. As the mice grew older, the transporter that brought the enzyme past the protective blood-brain barrier was lost.
"We found that the right amount of epinephrine allowed the enzyme to pass into the brain of older mice, which means we reinduced the way to get the enzyme where it is needed," Banks says.
Epinephrine is a drug that treats cardiac arrest and is given to open the airways of asthma patients who have difficulty breathing. Discovering epinephrine as the transportation key to unlock the blood-brain barrier for the missing enzyme was "a shot in the dark," Banks says.
"High doses of epinephrine can destroy the blood brain barrier and let everything into the brain, which is toxic," Banks says. "We tested three things. One didn't work at all. One worked partially and epinephrine worked incredibly well."
The finding changes how scientists look at getting medications through the blood-brain barrier, he says, and could have implications for treating other diseases such as Alzheimer's disease and obesity.
Instead of viewing the blood-brain barrier as an obstacle to fight, researchers should consider it something to finesse, using its special features to help in drug delivery, Banks adds.
"The field has approached the problem as if you have a Volkswagen that can get across the street and you put your cargo on it so the cargo can get there too. We've found that trying to transport the cargo changes the Volkswagen and the Volkswagen can no longer get across."
The research was funded by the National Institutes of Health, The Sanfilippo Syndrome Medical Research Foundation and VA Merit Review.
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