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"Chemical chaperones" might be able to help a
mutant protein (green) do its job of removing excess cholesterol
(blue) from cells.
Image � by Washington University in St. Louis
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Daniel S. Ory, M.D., associate professor of
medicine, and colleagues in the Center for Cardiovascular Research
originally began to study Niemann-Pick type C disease because of its
link to cholesterol metabolism - the genetic
abnormality at the root of the disease serves as a tool for
investigating how cholesterol moves about in cells.
Niemann-Pick type C, the rarest form of Niemann-Pick disease, usually
affects school-aged children, but the disease may occur at any time
from early infancy to adulthood. Symptoms may include unsteadiness of
gait, clumsiness, slurred speech, learning difficulties, progressive
intellectual decline, seizures and tremors. Niemann-Pick type C
disease is fatal, and no life-extending treatment exists.
As the result of their latest research, Ory and colleagues want to
follow up with an investigation of a different treatment modality than
has previously been proposed. Prior avenues of treatment research
emphasized using gene therapy to repair the genetic defect, but such
an approach is fraught with numerous difficulties. Ory's group
believes that Niemann-Pick type C and other diseases like it might be
treated more readily with chemical compounds able to compensate for
the effect of the disease's underlying genetic mutation.
Niemann-Pick type C disease is a recessive inherited trait that can
originate in one of more than 200 different mutations in the NPC1 gene,
which lies on chromosome 18. The mutations lead to production of
abnormal NPC1 protein. Normally, NPC1 protein plays an essential role
in moving cholesterol out of cells, and if it doesn't function,
cholesterol and other lipids accumulate.
Most scientists assumed that Niemann-Pick type C mutations produced
NPC1 protein that didn't work correctly. So when a routine test in the
Ory lab of a mutated NPC1 protein showed that the protein was in fact
active in living cells, the researchers did a double take.
"It is unequivocal that the mutation causes disease in human patients,"
says Ory, also associate professor of cell biology and physiology. "Yet
the mutated protein seemed functional when we introduced it into cells."
When they looked for the explanation for this aberration, Ory and
colleagues found that a small proportion of the mutant protein
actually could do the job of normal NPC1 protein. It turned out that
the mutation caused most newly minted NPC1 protein molecules to fold
into the wrong shape or to assume their final shape slowly so that the
cell's quality control checkpoints rejected them. But some of the
mutant protein molecules assumed the correct shape and made it to
their proper destination.
That suggested to the team that Niemann-Pick type C disease possibly
could be treated with chemicals that assist the mutant proteins
produced in patients. Ory refers to these as chemical chaperones and
indicates this approach could help the large NPC1 proteins during the
process of folding their long, complex chains so that more of the
mutant proteins fold properly and pass through the cell's quality
control checkpoints.
In collaboration with the National Institutes of Health Chemical
Genomics Center, Ory will next screen more than 200,000 compounds to
see which ones increase the amount of mutant NPC1 that folds into a
functional form.
"The screening can be done in as little as two weeks because the
facility in Rockville, Md., has a huge library of compounds and
state-of-the-art robotic equipment that can perform the tests at very
high speed," Ory explains. "Then we will bring the compounds that show
a positive effect to our laboratory and validate them on cell lines
from Niemann-Pick patients. After that we will work with a
pharmaceutical partner to take the ones that are effective in cells
and make sure they will be safe and effective in people."
Although Niemann-Pick disorders are rare, affecting fewer than 2,000
people worldwide, Ory says that it is likely the chemical chaperone
approach to therapy could also be useful for other disorders caused by
genetic mutations that lead to protein misfolding. This includes
cystic fibrosis, a lung and digestive system disorder that affects
70,000 children and adults around the world.
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