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Research Article

Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

Leslie B. Gordon, Monica E. Kleinman, David T. Miller, Donna S. Neuberg, Anita Giobbie-Hurder, Marie Gerhard-Herman, Leslie B. Smoot, Catherine M. Gordon, Robert Cleveland, Brian D. Snyder, Brian Fligor, W. Robert Bishop, Paul Statkevich, Amy Regen, Andrew Sonis, Susan Riley, Christine Ploski, Annette Correia, Nicolle Quinn, Nicole J. Ullrich, Ara Nazarian, Marilyn G. Liang, Susanna Y. Huh, Armin Schwartzman, and Mark W. Kieran
  1. Departments of aAnesthesia,
  2. dMedicine,
  3. eLaboratory Medicine
  4. jCardiology,
  5. mRadiology,
  6. nOrthopedics,
  7. pOtolaryngology and Communication Enhancement
  8. rDentistry,
  9. sPhysical Therapy and Occupational Therapy Services, and
  10. vNeurology Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
  11. Divisions of bCritical Care Medicine,
  12. fGenetics,
  13. kAdolescent Medicine,
  14. lEndocrinology,
  15. uGastroenterology and Nutrition,
  16. wDermatology, and
  17. xHematology-Oncology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
  18. cDepartment of Pediatrics, Hasbro Children’s Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02903;
  19. gDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215;
  20. hDepartment of Biostatistics and Harvard School of Public Health, Boston, MA 02115;
  21. iDepartment of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
  22. qMerck Research Laboratories, Kenilworth, NJ 07033;
  23. tClinical Translational Study Unit, Boston Children’s Hospital, Boston, MA 02115;
  24. oCenter for Advanced Orthopaedic Studies, Department of Orthopaedics, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; and
  25. yDivision of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215

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PNAS October 9, 2012 109 (41) 16666-16671; https://doi.org/10.1073/pnas.1202529109
Leslie B. Gordon
Departments of aAnesthesia,
Divisions of bCritical Care Medicine,
cDepartment of Pediatrics, Hasbro Children’s Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02903;
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  • For correspondence: Leslie_Gordon@brown.edu mark_kieran@dfci.harvard.edu
Monica E. Kleinman
Departments of aAnesthesia,
Divisions of bCritical Care Medicine,
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David T. Miller
dMedicine,
eLaboratory Medicine
fGenetics,
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Donna S. Neuberg
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;
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Anita Giobbie-Hurder
gDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215;
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Marie Gerhard-Herman
iDepartment of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
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Leslie B. Smoot
jCardiology,
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Catherine M. Gordon
cDepartment of Pediatrics, Hasbro Children’s Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02903;
kAdolescent Medicine,
lEndocrinology,
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Robert Cleveland
mRadiology,
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Brian D. Snyder
nOrthopedics,
oCenter for Advanced Orthopaedic Studies, Department of Orthopaedics, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; and
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Brian Fligor
pOtolaryngology and Communication Enhancement
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W. Robert Bishop
qMerck Research Laboratories, Kenilworth, NJ 07033;
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Paul Statkevich
qMerck Research Laboratories, Kenilworth, NJ 07033;
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Amy Regen
rDentistry,
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Andrew Sonis
rDentistry,
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Susan Riley
sPhysical Therapy and Occupational Therapy Services, and
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Christine Ploski
sPhysical Therapy and Occupational Therapy Services, and
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Annette Correia
sPhysical Therapy and Occupational Therapy Services, and
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Nicolle Quinn
tClinical Translational Study Unit, Boston Children’s Hospital, Boston, MA 02115;
uGastroenterology and Nutrition,
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Nicole J. Ullrich
vNeurology Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Ara Nazarian
oCenter for Advanced Orthopaedic Studies, Department of Orthopaedics, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; and
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Marilyn G. Liang
dMedicine,
wDermatology, and
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Susanna Y. Huh
dMedicine,
uGastroenterology and Nutrition,
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Armin Schwartzman
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;
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Mark W. Kieran
xHematology-Oncology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
yDivision of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
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  • For correspondence: Leslie_Gordon@brown.edu mark_kieran@dfci.harvard.edu
  1. Edited* by Francis S. Collins, National Institutes of Health, Bethesda, MD, and approved August 13, 2012 (received for review February 16, 2012)

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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.

  • SCH66336
  • laminopathy
  • cardiovascular disease
  • translational medicine

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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Clinical improvement in progeria with an FTI
Leslie B. Gordon, Monica E. Kleinman, David T. Miller, Donna S. Neuberg, Anita Giobbie-Hurder, Marie Gerhard-Herman, Leslie B. Smoot, Catherine M. Gordon, Robert Cleveland, Brian D. Snyder, Brian Fligor, W. Robert Bishop, Paul Statkevich, Amy Regen, Andrew Sonis, Susan Riley, Christine Ploski, Annette Correia, Nicolle Quinn, Nicole J. Ullrich, Ara Nazarian, Marilyn G. Liang, Susanna Y. Huh, Armin Schwartzman, Mark W. Kieran
Proceedings of the National Academy of Sciences Oct 2012, 109 (41) 16666-16671; DOI: 10.1073/pnas.1202529109

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Clinical improvement in progeria with an FTI
Leslie B. Gordon, Monica E. Kleinman, David T. Miller, Donna S. Neuberg, Anita Giobbie-Hurder, Marie Gerhard-Herman, Leslie B. Smoot, Catherine M. Gordon, Robert Cleveland, Brian D. Snyder, Brian Fligor, W. Robert Bishop, Paul Statkevich, Amy Regen, Andrew Sonis, Susan Riley, Christine Ploski, Annette Correia, Nicolle Quinn, Nicole J. Ullrich, Ara Nazarian, Marilyn G. Liang, Susanna Y. Huh, Armin Schwartzman, Mark W. Kieran
Proceedings of the National Academy of Sciences Oct 2012, 109 (41) 16666-16671; DOI: 10.1073/pnas.1202529109
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