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 Posted: Fri Oct 10, 2008 11:36 pm Post subject: A farnesyltransferase inhibitor prevents both the onset and |
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Proc Natl Acad Sci U S A. 2008 Oct 6. [Epub ahead of print]
A farnesyltransferase inhibitor prevents both the onset and late
progression of cardiovascular disease in a progeria mouse model.
Capell BC, Olive M, Erdos MR, Cao K, Faddah DA, Tavarez UL, Conneely
KN, Qu X, San H, Ganesh SK, Chen X, Avallone H, Kolodgie FD, Virmani
R, Nabel EG, Collins FS.
Genome Technology Branch, National Human Genome Research Institute,
National Institutes of Health, Bethesda, MD 20892-8004;
Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic form
of human premature aging. Death occurs at a mean age of 13 years,
usually from heart attack or stroke. Almost all cases of HGPS are
caused by a de novo point mutation in the lamin A (LMNA) gene that
results in production of a mutant lamin A protein termed progerin.
This protein is permanently modified by a lipid farnesyl group, and
acts as a dominant negative, disrupting nuclear structure. Treatment
with farnesyltransferase inhibitors (FTIs) has been shown to prevent
and even reverse this nuclear abnormality in cultured HGPS
fibroblasts. We have previously created a mouse model of HGPS that
shows progressive loss of vascular smooth muscle cells in the media of
the large arteries, in a pattern that is strikingly similar to the
cardiovascular disease seen in patients with HGPS. Here we show that
the dose-dependent administration of the FTI tipifarnib (R115777,
Zarnestra) to this HGPS mouse model can significantly prevent both the
onset of the cardiovascular phenotype as well as the late progression
of existing cardiovascular disease. These observations provide
encouraging evidence for the current clinical trial of FTIs for this
rare and devastating disease.
PMID: 18838683 [PubMed - as supplied by publisher] |
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