Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Edited* by Francis S. Collins, National Institutes of Health, Bethesda, MD, and approved August 13, 2012 (received for review February 16, 2012)
Abstract
Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.
Footnotes
↵1L.B.G., M.E.K., and D.T.M. contributed equally to this work.
- ↵2To whom correspondence may be addressed. E-mail: Leslie_Gordon{at}brown.edu or mark_kieran{at}dfci.harvard.edu.
Author contributions: L.B.G., M.E.K., D.T.M., D.S.N., A.G.-H., and M.W.K. designed research; L.B.G., M.E.K., D.T.M., M.G.-H., L.B.S., C.M.G., R.C., B.D.S., B.F., A.R., A. Sonis, S.R., C.P., A.C., N.Q., N.J.U., A.N., M.G.L., S.Y.H., and M.W.K. performed research; W.R.B. and P.S. contributed new reagents/analytic tools; L.B.G., M.E.K., D.T.M., D.S.N., A.G.-H., M.G.-H., W.R.B., P.S., A. Schwartzman, and M.W.K. analyzed data; and L.B.G., M.E.K., D.T.M., D.S.N., A.G.-H., M.G.-H., L.B.S., C.M.G., R.C., B.D.S., B.F., A.R., A. Sonis, S.R., C.P., A.C., N.J.U., A.N., M.G.L., S.Y.H., and M.W.K. wrote the paper.
Conflict of interest statement: W.R.B. and P.S. are employees of Merck Pharmaceutical, the company that supplied the experimental agent for this clinical trial. L.B.G. is the mother of a child with progeria who participated in this study.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1202529109/-/DCSupplemental.
Freely available online through the PNAS open access option.
Clinical improvement in progeria with an FTI
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