In vitro and in vivo effects of farnesyltransferase inhibitors for Hutchinson-Gilford progeria syndrome. B.C. Capell¹, M.R. Erdos¹, M. Eriksson², R. Varga¹, M. Olive¹, F. Kolodgie³, H. Avallone³, H. San¹, X. Qu¹, L.B. Gordon⁴, R. Virmani³, E.G. Nabel^1,5, W.A. Gahl¹, F.S. Collins¹. 1) NHGRI, NIH, Bethesda, MD; 2) Karolinska Institutet, Huddinge, Sweden; 3) CVPath, Inc., Gaithersburg, MD; 4) Brown University, Providence, RI; 5) NHLBI, NIH, Bethesda, MD.
   Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder of premature aging and accelerated cardiovascular disease. HGPS is almost always caused by a de novo point mutation in the lamin A (LMNA) gene that activates a cryptic splice donor site, producing a mutant protein, termed progerin. Wild-type prelamin A is anchored to the nuclear envelope by a modification of the C-terminal CAAX motif by a farnesyl isoprenoid lipid. Cleavage of the terminal 15 amino acids and the farnesyl group releases mature lamin A from this tether. This cleavage site is deleted in progerin. We hypothesized that retention of the farnesyl group causes progerin to remain anchored in the nuclear membrane, disrupting the nuclear scaffold and causing nuclear blebbing characteristic of HGPS. If so, blocking farnesylation should decrease progerin toxicity. Blocking farnesylation of progerin in transiently transfected cells with farnesyltransferase inhibitors (FTIs) has been shown to restore normal nuclear architecture. Treatment of early and late passage human HGPS fibroblasts with FTIs also reduces nuclear blebbing. Therefore, we administered the FTI, tipifarnib (R115777, Zarnestra), to a transgenic mouse model of HGPS that was created by recombineering a 164 kb human BAC containing the LMNA gene to incorporate the 1824C>T (G608G) mutation. Mice from a stable transgenic line express the mutant LMNA RNA and protein (progerin) products, and display a progressive loss of vascular smooth muscle cells, strikingly similar to the cardiovascular disease of HGPS. Early results in 5 month-old animals treated with R115777 suggest little or no dropout of vascular smooth muscle cells in the media of large arteries, providing encouragement that this drug therapy may work. Based on these observations, we believe that there is sufficient evidence to initiate a clinical trial with an FTI for children with progeria later this year.