A Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria
- 17 March 2006
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 311 (5767), 1621-1623
- https://doi.org/10.1126/science.1124875
Abstract
Progerias are rare genetic diseases characterized by premature aging. Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl–prelamin A disrupts this scaffolding, leading to misshapen nuclei. Previous studies have shown that farnesyltransferase inhibitors (FTIs) reverse this cellular abnormality. We tested the efficacy of an FTI (ABT-100) in Zmpste24 -deficient mice, a mouse model of progeria. The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. These results suggest that FTIs may have beneficial effects in humans with progeria.Keywords
This publication has 18 references indexed in Scilit:
- Thematic Review Series: Lipid Posttranslational Modifications. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria—new evidence suggesting that protein farnesylation could be important for disease pathogenesisJournal of Lipid Research, 2005
- Homozygous and Compound Heterozygous Mutations in ZMPSTE24 Cause the Laminopathy Restrictive DermopathyJournal of Investigative Dermatology, 2005
- Incomplete processing of mutant lamin A in Hutchinson–Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibitionHuman Molecular Genetics, 2005
- Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane‐refractory/resistant nonsmall cell lung carcinomaCancer, 2005
- Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotypeJournal of Medical Genetics, 2005
- Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursorsHuman Molecular Genetics, 2005
- Antitumor Activity of Orally Bioavailable Farnesyltransferase Inhibitor, ABT-100, Is Mediated by Antiproliferative, Proapoptotic, and Antiangiogenic Effects in Xenograft ModelsClinical Cancer Research, 2005
- A Phase I Trial of the Novel Farnesyl Protein Transferase Inhibitor, BMS-214662, in Combination with Paclitaxel and Carboplatin in Patients with Advanced CancerClinical Cancer Research, 2005
- Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myelomaBlood, 2004
- The Hutchinson-Gilford progeria syndrome: Report of 4 cases and review of the literatureThe Journal of Pediatrics, 1972