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Anti-Cancer Drug May Hold Potential for Treatment of
Aging
A potential therapy for children suffering from
Hutchinson-Gilford Progeria Syndrome
Aug. 30, 2005 - A class of experimental anti-cancer
drugs also shows surprising promise in laboratory studies for treating a
fatal genetic disorder – progeria - that causes premature aging in
children. The discovery, scientist hope, may also shed light on
treatment for aging and atherosclerotic disease for senior citizens and
other adults.
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“What really interested me in this research in
the first place were the potential links to aging and
atherosclerotic disease.” - Brian Capell |
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In a study published Monday in the online edition
of the Proceedings of the National Academy of Sciences (PNAS), Brian
Capell and his colleagues at NHGRI reported that drugs known as
farnesyltransferase inhibitors (FTIs), which are currently being tested
in people with myeloid leukemia, neurofibromatosis and other conditions,
might also provide a potential therapy for children suffering from
Hutchinson-Gilford Progeria Syndrome, commonly referred to as progeria.
A related study from Stephen Young, M.D., and colleagues at the
University of California at Los Angeles is being published in the same
issue of PNAS.
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The research team is led by the National Human
Genome Research Institute (NHGRI), part of the National Institutes of
Health (NIH).
There are currently no treatments for progeria,
which is a genetic disorder estimated to affect one child in 4 million.
When they are born, children with progeria appear normal. But, as they
grow older, they experience growth retardation and show dramatically
accelerated symptoms of aging — namely hair loss, skin wrinkling and fat
loss. Accelerated cardiovascular disease also ensues, typically causing
death from heart attack or stroke at about the age of 12.
“Our findings show that FTIs, originally developed
for cancer, are capable of reversing the dramatic nuclear structure
abnormalities that are the hallmark of cells from children with progeria.
This is a stunning surprise, rather like finding out that the key to
your house also works in the ignition of your car," said NHGRI Director
Francis S. Collins, M.D., Ph.D., who is the study’s senior author.
The new work involved using FTIs to treat skin
cells taken from progeria patients and grown in laboratory conditions.
If upcoming studies in a mouse model validate the results of the cell
experiments and translate into improvements in the animals’ conditions,
a clinical trial of FTIs in children with progeria may begin as early as
next spring, researchers said.
Dr. Collins and his colleagues discovered in April
2003 that mutations in the lamin A (LMNA) gene cause progeria, spurring
renewed interest among researchers to study this rare syndrome. Among
those were Capell, a New York University medical student participating
in the Howard Hughes Medical Institute/NIH (HHMI/NIH) Research Scholars
Program. In July 2004, he joined Dr. Collins’ lab and immediately set
his sights on understanding the molecular basis of progeria.
“What really interested me in this research in the
first place were the potential links to aging and atherosclerotic
disease,” said Capell. Indeed, understanding progeria at the molecular
level may illuminate the general processes involved in normal human
aging.
The LMNA gene codes for a protein called lamin A,
which constitutes a major component of the scaffold-like network of
proteins just inside the cell’s nuclear membrane, called the lamina. The
gene mutation implicated in progeria causes a section of 50 amino acids
within the lamin A protein to be deleted, resulting in a mutated protein
that is called progerin. This protein fails to integrate properly into
the lamina, thereby disrupting the nuclear scaffolding and causing gross
disfigurement of the nucleus. Cells with progerin have a nucleus with a
characteristic “blebbed,” or lobular, shape.
To find its way to the lamina, lamin A carries two
tags, rather like ZIP codes, that help to direct the protein’s travels.
One tag at the end of lamin A instructs another protein to modify it
through a process called farnesylation. Farnesylation tethers lamin A to
the inner nuclear membrane. Once there, a second tag within the protein
signals an enzyme to cleave off the terminal portion of the protein,
including the farnesyl group, freeing lamin A to integrate properly into
the nuclear lamina.
Because progerin carries the farnesylation tag but
lacks the second cleavage tag, Capell speculated that progerin was
becoming permanently stuck to the inner nuclear membrane. There, he
suspected, it enmeshed other scaffolding proteins, preventing their
proper integration into the lamina. If progerin’s tendency to stick to
the inner nuclear membrane is indeed the culprit in nuclear blebbing and
the root of the progeria defect, Capell and his colleagues reasoned that
they could prevent these defects by blocking farnesylation of progerin.
The researchers’ hunch proved correct. When they
changed one amino acid within progerin’s farnesylation tag to prevent
the addition of a farnesyl group and tested the effect in cells grown in
the laboratory, progerin did not anchor itself to the inner nuclear
membrane and instead clumped within the nucleus. Moreover, they observed
no nuclear blebbing.
The researchers then tried treating the cells
carrying progerin with FTIs, which are drugs originally developed to
inhibit certain cancer-causing proteins that require farnesylation for
function. FTIs are now being tested in phase III clinical trials of
patients with myeloid leukemia. So far, clinical trials using FTIs have
found little toxicity, even when the drug treatment significantly raises
levels of unfarnesylated proteins.
After FTI treatment, the progerin-carrying cells
showed no blebbing. More importantly, researchers saw the same effect
when they used FTIs to treat cells grown from skin biopsies of progeria
patients: Cell blebbing decreased to near normal levels.
In addition to Capell and his colleagues in NHGRI’s
Genome Technology Branch, researchers from the University of North
Carolina at Chapel Hill and the University of Michigan School of Public
Health in Ann Arbor took part in the study.
The HHMI/NIH Research Scholars Program gives
outstanding medical and dental students the opportunity to conduct
biomedical research under the direct mentorship of senior NIH research
scientists.
NHGRI is one of the 27 institutes and centers at
NIH, which is an agency of the Department of Health and Human Services.
The NHGRI Division of Intramural Research develops and implements
technology to understand, diagnose and treat genomic and genetic
diseases. Additional information about NHGRI can be found at its Web
site:
www.genome.gov.
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