Revisiting a Premature Aging Drug

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Science  19 Sep 2008:
Vol. 321, Issue 5896, pp. 1606
DOI: 10.1126/science.321.5896.1606a

Children with the rare disorder Hutchinson-Gilford progeria syndrome (HGPS) develop a constellation of health problems typically seen in the geriatric population, including severe atherosclerosis and osteoporosis, and most affected individuals die as teenagers. The disease-causing mutation lies in the LMNA gene, which encodes the nuclear scaffold protein lamin A, and it results in the production of an unprocessed form of lamin A that aberrantly retains a farnesyl lipid anchor and induces structural changes in the cell nucleus. The observations that farnesyltransferase inhibitors (FTIs: drugs that inhibit the enzyme that attaches the farnesyl tail to proteins) partially reversed the nuclear changes in cultured cells and ameliorated disease symptoms in mouse models of HGPS, led to the initiation of a clinical trial to test these drugs in children with the disease.

New results suggest that the concept motivating this clinical trial may require revision. To test the hypothesis that the HGPS-associated lamin A is toxic because of its farnesyl group, Yang et al. generated mice expressing a mutant version of lamin A that contained not only the disease-causing mutation but an additional mutation that prevented the protein from being farnesylated. Surprisingly, these mice developed the same spectrum of HGPS-like phenotypes as did mice expressing the farnesylated protein, albeit in a milder form. Thus, farnesylation of lamin A is unlikely to be a major contributor to the pathogenesis of HGPS, and the mechanism underlying the therapeutic efficacy of FTIs in the earlier preclinical studies remains unclear. — PAK

J. Clin. Invest. 118, 10.1172/JCI35876 (2008).

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