TSRI Scientists Develop Potential New Treatment for Gaucher
A group of scientists at The Scripps Research Institute (TSRI)
have developed a compound that could potentially be used as
a new treatment for Gaucher disease, the most common genetic
disorder affecting Jewish people of Eastern European ancestry.
Although not tested in humans, the compound has shown great
promise in human cell lines cultured from patients who suffer
from the disease.
Patients with Gaucher disease may bruise easily due to low
blood platelets, and they may have enlargement of the liver
and spleen. Sometimes they experience fatigue due to anemia.
The disease also causes cells in the bone marrow to become
engorged with a fatty storage material, which may lead to
bone lesions, weakening the skeleton, and sometimes resulting
in painful fractures. In some instances, the disease also
impairs the function of the lungs.
In an article that will be published in an upcoming issue
of the journal Proceedings of the National Academy of Sciences,
the TSRI group describes using small molecules to partially
correct the genetic defect that underlies most cases of Gaucher
disease. The defect prevents a crucial metabolic enzyme from
reaching the location in the cell where it normally functions,
but the small molecules act as "chaperones," guiding the mutant
enzyme to the right location and allowing it to survive and
"This is an entirely new approach to the disease," says
TSRI Professor Ernest Beutler, who is one of the authors of
the study and one of the world's leading experts on Gaucher
disease and similar metabolic disorders. Beutler's laboratory
was the first to clone the gene responsible for Gaucher disease
in the mid-1980s.
"And it may be less costly and more convenient than the
current treatment," adds Jeffery W. Kelly, who is the Lita
Annenberg Hazen Professor of Chemistry and vice president
of academic affairs at TSRI. Kelly led the research effort
along with the study's first author, Anu Sawkar, a Ph.D. student
in TSRI's Kellogg School of Science and Technology.
A New Approach to an Old Disease
Gaucher disease, which is named after the French dermatologist
Phillipe Gaucher, who first described the condition in 1882,
is a genetic disease caused by heritable defects of an important
metabolic enzyme called lysosomal beta-glucosidase. People
with Gaucher disease have one or more defects in their beta-glucosidase
genes, and these defects corrupt their beta-glucosidase enzyme.
Some of these corrupted enzymes are apparently unstable because
they cannot fold properly into their correct three-dimensional
Normally beta-glucosidase resides and functions in macrophage
lysosomesthe sac-like organelles that recycle macromolecules
inside cellswhere it breaks down fatty substances known
as glucosylceramides. But the corrupted, mutant enzyme may
fail to reach the lysosome, and as a result, the fatty glucosylceramides
accumulate there. The macrophages become engorged with glucosylceramide-swollen
lysosomes, which causes problems in the spleen, liver, lungs,
bone marrowand, in rare cases, the brain.
There are dozens of different mutations that can cause Gaucher
disease, and the prevalence of the disease varies widely in
different ethnic populations. Most at risk for the disease
are individuals of Eastern European Jewish ancestry (the so-called
Ashkenazi Jews), among whom about 1 in 14 carry one copy of
one of the mutations of beta-glucosidase. As a result, the
prevalence of Gaucher disease among Ashkenazi Jews has been
estimated to be about 1 in 800. In the general population,
about 1 in every 40,000 to 100,000 people have Gaucher disease.
The current approaches to treating Gaucher disease involve
replacing the deficient enzyme, thereby breaking down the
accumulated glucosylceramide and preventing it from accumulating.
Enzyme replacement therapy is a highly effective way to restore
people to good health, but it has a couple of serious drawbacks.
The enzyme has to be infused intravenously or through a
surgically implanted catheterusually in a doctor's officea
process that takes several hours and must be repeated every
one or two weeks. Enzyme replacement therapy is also extremely
expensive, costing between $100,000 and $750,000 per year
per patient. And the therapy is not effective at treating
neurological complications of Gaucher disease.
Now Kelly, Beutler, and their colleagues at TSRI report
positive results on a radically different approach that may
address some of the problems with enzyme replacement therapy.
Rather than replacing the mutant enzyme, says Kelly, "We use
a small molecule to partially correct [its] imperfections."
Their small molecule "chaperone" stabilizes the mutant beta-glucosidase
enzyme, helping it to fold properly and find its way to the
lysosome, where it can degrade the fatty substance.
The chaperone targets the most common Gaucher mutation,
which is referred to as "1226G" or "N370S." Virtually every
Jewish patient with Gaucher disease has this beta-glucosidase
A therapy based on these chaperones has the potential to
be much more convenient and less costly than enzyme replacement,
because small molecules could be taken orally and would be
cheaper to mass-produce than whole enzymes. In addition, small
molecules can be found that cross the blood-brain barrier,
and perhaps address the neurological complications of Gaucher
disease, if they are caused by mutants that respond to chaperone
The article, "Chemical chaperones increase the cellular
activity of N370S beta-glucosidase: A therapeutic strategy
for Gaucher disease" was authored by Anu R. Sawkar, Wei-Chieh
Cheng, Ernest Beutler, Chi-Huey Wong, William E. Balch, and
Jeffery W. Kelly, and appears in the online edition of the
journal Proceedings of the National Academy of Sciences
the week of November 4, 2002. The article will appear in print
later this year.
This work was supported by the Skaggs Institute for Chemical
Biology, the Lita Annenberg Hazen Foundation, the Stein Endowment
Fund, and a National Science Foundation Predoctoral Fellowship.