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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
aging.
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.
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 cells 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 proteins 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 progerins 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 progerins 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 NHGRIs 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. 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 http://www.nih.gov.
Tags: health green
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