BETHESDA, Md., Mon., Aug. 29, 2005 -- In a surprising development, aresearch team led by the National Human Genome Research Institute(NHGRI), part of the National Institutes of Health (NIH), has foundthat a class of experimental anti-cancer drugs also shows promise inlaboratory studies for treating a fatal genetic disorder that causespremature aging.
In a study published Monday in the online edition of the Proceedingsof the National Academy of Sciences (PNAS), Brian Capell and hiscolleagues at NHGRI reported that drugs known as farnesyltransferaseinhibitors (FTIs), which are currently being tested in people withmyeloid leukemia, neurofibromatosis and other conditions, might alsoprovide a potential therapy for children suffering fromHutchinson-Gilford Progeria Syndrome, commonly referred to as progeria.A related study from Stephen Young, M.D., and colleagues at theUniversity of California at Los Angeles is being published in the sameissue of PNAS.
There are currently no treatments for progeria, which is agenetic disorder estimated to affect one child in 4 million. When theyare born, children with progeria appear normal. But, as they growolder, they experience growth retardation and show dramaticallyaccelerated symptoms of aging -- namely hair loss, skin wrinkling andfat loss. Accelerated cardiovascular disease also ensues, typicallycausing 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 abnormalitiesthat are the hallmark of cells from children with progeria. This is astunning surprise, rather like finding out that the key to your housealso 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 fromprogeria patients and grown in laboratory conditions. If upcomingstudies in a mouse model validate the results of the cell experimentsand translate into improvements in the animals' conditions, a clinicaltrial of FTIs in children with progeria may begin as early as nextspring, researchers said.
Dr. Collins and his colleagues discovered in April 2003 thatmutations in the lamin A (LMNA) gene cause progeria, spurring renewedinterest among researchers to study this rare syndrome. Among thosewere Capell, a New York University medical student participating in theHoward Hughes Medical Institute/NIH (HHMI/NIH) Research ScholarsProgram. In July 2004, he joined Dr. Collins' lab and immediately sethis sights on understanding the molecular basis of progeria.
"What really interested me in this research in the first placewere the potential links to aging and atherosclerotic disease," saidCapell. Indeed, understanding progeria at the molecular level mayilluminate the general processes involved in normal human aging.
The LMNA gene codes for a protein called lamin A, whichconstitutes a major component of the scaffold-like network of proteinsjust inside the cell's nuclear membrane, called the lamina. The genemutation implicated in progeria causes a section of 50 amino acidswithin the lamin A protein to be deleted, resulting in a mutatedprotein that is called progerin. This protein fails to integrateproperly into the lamina, thereby disrupting the nuclear scaffoldingand causing gross disfigurement of the nucleus. Cells with progerinhave 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. Onetag at the end of lamin A instructs another protein to modify itthrough a process called farnesylation. Farnesylation tethers lamin Ato the inner nuclear membrane. Once there, a second tag within theprotein signals an enzyme to cleave off the terminal portion of theprotein, including the farnesyl group, freeing lamin A to integrateproperly into the nuclear lamina.
Because progerin carries the farnesylation tag but lacks thesecond cleavage tag, Capell speculated that progerin was becomingpermanently stuck to the inner nuclear membrane. There, he suspected,it enmeshed other scaffolding proteins, preventing their properintegration into the lamina. If progerin's tendency to stick to theinner nuclear membrane is indeed the culprit in nuclear blebbing andthe root of the progeria defect, Capell and his colleagues reasonedthat they could prevent these defects by blocking farnesylation ofprogerin.
The researchers' hunch proved correct. When they changed oneamino acid within progerin's farnesylation tag to prevent the additionof a farnesyl group and tested the effect in cells grown in thelaboratory, progerin did not anchor itself to the inner nuclearmembrane and instead clumped within the nucleus. Moreover, theyobserved no nuclear blebbing.
The researchers then tried treating the cells carrying progerinwith FTIs, which are drugs originally developed to inhibit certaincancer-causing proteins that require farnesylation for function. FTIsare now being tested in phase III clinical trials of patients withmyeloid leukemia. So far, clinical trials using FTIs have found littletoxicity, even when the drug treatment significantly raises levels ofunfarnesylated proteins.
After FTI treatment, the progerin-carrying cells showed noblebbing. More importantly, researchers saw the same effect when theyused 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 GenomeTechnology Branch, researchers from the University of North Carolina atChapel Hill and the University of Michigan School of Public Health inAnn Arbor took part in the study.
The HHMI/NIH Research Scholars Program gives outstandingmedical and dental students the opportunity to conduct biomedicalresearch under the direct mentorship of senior NIH research scientists.
NHGRI is one of the 27 institutes and centers at NIH, which is anagency of the Department of Health and Human Services. The NHGRIDivision of Intramural Research develops and implements technology tounderstand, diagnose and treat genomic and genetic diseases. Additionalinformation about NHGRI can be found at its Web site: www.genome.gov.
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