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Anti-Cancer Drugs has promise for Hutchinson-Gilford Progeria Syndrome

>Anti-Cancer Drugs has promise for Hutchinson-Gilford Progeria Syndrome

Anti-Cancer Drugs has promise for Hutchinson-Gilford Progeria Syndrome
NIH release
September 1, 2005

Bethesda, Maryland — In a surprising development,
a research team led by the National Human Genome Research
Institute (NHGRI), part of the National Institutes of
Health (NIH), has found that a class of experimental
anti-cancer drugs also shows promise in laboratory studies
for treating a fatal genetic disorder that causes premature

In a study published Monday in the online edition of
the Proceedings of the National Academy of Sciences
), 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.

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

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:

The National Institutes of Health (NIH) — The
Nation’s Medical Research Agency
— is comprised
of 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services.
It is the primary Federal agency for conducting and
supporting basic, clinical, and translational medical
research, and investigates the causes, treatments,
and cures for both common and rare diseases. For more
information about NIH and its programs, visit

This is a NIH news release. The original version appears here

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