Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome
- Departments of aAnesthesia,
- dMedicine,
- eLaboratory Medicine
- jCardiology,
- mRadiology,
- nOrthopedics,
- pOtolaryngology and Communication Enhancement
- rDentistry,
- sPhysical Therapy and Occupational Therapy Services, and
- vNeurology Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
- Divisions of bCritical Care Medicine,
- fGenetics,
- kAdolescent Medicine,
- lEndocrinology,
- uGastroenterology and Nutrition,
- wDermatology, and
- xHematology-Oncology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
- cDepartment of Pediatrics, Hasbro Children’s Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02903;
- gDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215;
- hDepartment of Biostatistics and Harvard School of Public Health, Boston, MA 02115;
- iDepartment of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
- qMerck Research Laboratories, Kenilworth, NJ 07033;
- tClinical Translational Study Unit, Boston Children’s Hospital, Boston, MA 02115;
- oCenter for Advanced Orthopaedic Studies, Department of Orthopaedics, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; and
- yDivision of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
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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.
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