New direction for research into Sly Syndrome

Aug 9 2004

Findings by a Saint Louis University research team led by the scientist who discovered Sly Syndrome 32 years ago point to a new direction for research into the rare genetic disorder that can cause bone deformities, vision and hearing loss, mental retardation and death in children.

The research is published in the Proceedings of the National Academy of Sciences Online Early Edition the week of Aug. 9.

"The importance of this research goes far beyond this rare disorder," said William Sly, M.D., chairman of the department of biochemistry and molecular biology at Saint Louis University School of Medicine. "It could potentially provide access to the brain for enzyme therapy in other similar diseases, most of which are more common than Sly Syndrome."

Sly Syndrome occurs in less than one in 250,000 births and is a progressive disorder that ranges in severity to extremely severe -– resulting in death -– to mild. It is caused by the deficiency of an enzyme called beta-glucuronidase, which leads to an accumulation of protein-sugar molecules known as mucopolysaccharides in many of the body's organs, including the brain. Enzyme replacement therapy -– injecting the missing enzyme into the body –- holds promise in treating physical problems caused by mucopolysaccharide accumulation in parts of the body other than the brain. The blood-brain barrier prevents the enzyme from reaching the brain.

But Saint Louis University researchers examining an animal model of Sly Syndrome previously had found that enzyme replacement therapy was effective in treating the brain if given while the mice were very young.

"Until now, the reason why the central nervous system of neonates, but not adults, responds to enzyme replacement therapy was unknown," said William A. Banks, M.D., an author of the article and a professor of geriatrics in the department of internal medicine and professor of pharmacological science at Saint Louis University School of Medicine.

The research discovered how injections of the missing enzyme to treat Sly Syndrome reached the brains of baby mice, but not of brains of adults.

"Here we report that the blood-brain barrier of neonatal mice possesses a transport system for the enzyme that is progressively lost with aging. In fact by adulthood, the blood-brain barrier has totally lost this transport capacity."

Until this discovery, researchers had assumed that the only way to get enzyme into the brain was to build some kind of delivery system which could cross the blood-brain barrier.

"But this research shows that the blood-brain barrier already has its own delivery system. Unfortunately, it shuts down when you reach adulthood," Banks said.

The blood-brain barrier continues to make the delivery molecule, which is the mannose-6 phosphate receptor (M6PR), but does not place it on the surface of the blood-brain barrier where it can transport enzyme. Instead the M6PR stays inside the blood-brain barrier cell.

"We've got to convince the blood-brain barrier to turn the delivery system back on."

The answer to switching the delivery system back on, Banks speculates, lies in the area of protein translocation –- the process that cells use to decide where they put the proteins they make.

"It becomes a molecular biology question. Really, it's a question of how does the cell decide which proteins it keeps inside and which it translocates to its surface. The whole question had been posed as a problem of inventing a blood-brain barrier delivery system," said Banks, who also is a staff physician at Veterans Affairs Medical Center in St. Louis.

"Now we have a new haystack to look in. Instead of learning how to build a truck to deliver the enzyme across the blood-brain barrier, we need to figure out how to get the stop light to switch back to green. In other words, how do we get the blood-brain barrier's truck to start delivery service again."

Added Sly, "Most lysosomal storage diseases are much more common than Sly Syndrome. And most of these also affect the central nervous system and could benefit immensely by a discovery that provides the means to deliver an enzyme across the blood-brain barrier after the newborn period."