Leslie B Gordon1, Monica E Kleinman2, Joe Massaro2, Ralph B D'Agostino2, Heather Shappell2, Marie Gerhard-Herman2, Leslie B Smoot2, Catherine M Gordon2, Robert H Cleveland2, Ara Nazarian2, Brian D Snyder2, Nicole J Ullrich2, V Michelle Silvera2, Marilyn G Liang2, Nicolle Quinn2, David T Miller2, Susanna Y Huh2, Anne A Dowton2, Kelly Littlefield2, Maya M Greer2, Mark W Kieran1. 1. From Departments of Anesthesia (L.B.G., M.E.K., A.A.D., K.L., M.M.G.), Cardiology (L.B.S.), Radiology (R.H.C., V.M.S.), Orthopedics (B.D.S.), Neurology (N.J.U.), Dermatology (M.G.L.), Genetics and Genomics (D.T.M.), Gastroenterology and Nutrition (S.Y.H.), and Hematology Oncology (M.W.K.), and Clinical Translational Study Unit (N.Q.), Boston Children's Hospital and Harvard Medical School, MA; Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI (L.B.G.); Department of Biostatistics, Boston University School of Public Health and Harvard Clinical Research Institute, MA (J.M., R.B.D., H.S.); Division of Cardiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (M.G.-H.); Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, OH (C.M.G.); Center for Advanced Orthopaedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (A.N.); and Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (M.W.K.). Leslie_Gordon@brown.edu Mark_Kieran@dfci.harvard.edu. 2. From Departments of Anesthesia (L.B.G., M.E.K., A.A.D., K.L., M.M.G.), Cardiology (L.B.S.), Radiology (R.H.C., V.M.S.), Orthopedics (B.D.S.), Neurology (N.J.U.), Dermatology (M.G.L.), Genetics and Genomics (D.T.M.), Gastroenterology and Nutrition (S.Y.H.), and Hematology Oncology (M.W.K.), and Clinical Translational Study Unit (N.Q.), Boston Children's Hospital and Harvard Medical School, MA; Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI (L.B.G.); Department of Biostatistics, Boston University School of Public Health and Harvard Clinical Research Institute, MA (J.M., R.B.D., H.S.); Division of Cardiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (M.G.-H.); Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, OH (C.M.G.); Center for Advanced Orthopaedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (A.N.); and Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (M.W.K.).
Abstract
BACKGROUND: Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. METHODS: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. RESULTS: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. CONCLUSIONS: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.
BACKGROUND:Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. METHODS: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. RESULTS: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. CONCLUSIONS: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.
Authors: Annachiara De Sandre-Giovannoli; Rafaëlle Bernard; Pierre Cau; Claire Navarro; Jeanne Amiel; Irène Boccaccio; Stanislas Lyonnet; Colin L Stewart; Arnold Munnich; Martine Le Merrer; Nicolas Lévy Journal: Science Date: 2003-04-17 Impact factor: 47.728
Authors: Leslie B Gordon; Joe Massaro; Ralph B D'Agostino; Susan E Campbell; Joan Brazier; W Ted Brown; Monica E Kleinman; Mark W Kieran Journal: Circulation Date: 2014-05-02 Impact factor: 29.690
Authors: Brian C Capell; Michael R Erdos; James P Madigan; James J Fiordalisi; Renee Varga; Karen N Conneely; Leslie B Gordon; Channing J Der; Adrienne D Cox; Francis S Collins Journal: Proc Natl Acad Sci U S A Date: 2005-08-29 Impact factor: 11.205
Authors: Maria Eriksson; W Ted Brown; Leslie B Gordon; Michael W Glynn; Joel Singer; Laura Scott; Michael R Erdos; Christiane M Robbins; Tracy Y Moses; Peter Berglund; Amalia Dutra; Evgenia Pak; Sandra Durkin; Antonei B Csoka; Michael Boehnke; Thomas W Glover; Francis S Collins Journal: Nature Date: 2003-04-25 Impact factor: 49.962
Authors: Shao H Yang; Margarita Meta; Xin Qiao; David Frost; Joy Bauch; Catherine Coffinier; Sharmila Majumdar; Martin O Bergo; Stephen G Young; Loren G Fong Journal: J Clin Invest Date: 2006-08 Impact factor: 14.808
Authors: Robert D Goldman; Dale K Shumaker; Michael R Erdos; Maria Eriksson; Anne E Goldman; Leslie B Gordon; Yosef Gruenbaum; Satya Khuon; Melissa Mendez; Renée Varga; Francis S Collins Journal: Proc Natl Acad Sci U S A Date: 2004-06-07 Impact factor: 11.205
Authors: Brian C Capell; Michelle Olive; Michael R Erdos; Kan Cao; Dina A Faddah; Urraca L Tavarez; Karen N Conneely; Xuan Qu; Hong San; Santhi K Ganesh; Xiaoyan Chen; Hedwig Avallone; Frank D Kolodgie; Renu Virmani; Elizabeth G Nabel; Francis S Collins Journal: Proc Natl Acad Sci U S A Date: 2008-10-06 Impact factor: 11.205
Authors: Melissa A Merideth; Leslie B Gordon; Sarah Clauss; Vandana Sachdev; Ann C M Smith; Monique B Perry; Carmen C Brewer; Christopher Zalewski; H Jeffrey Kim; Beth Solomon; Brian P Brooks; Lynn H Gerber; Maria L Turner; Demetrio L Domingo; Thomas C Hart; Jennifer Graf; James C Reynolds; Andrea Gropman; Jack A Yanovski; Marie Gerhard-Herman; Francis S Collins; Elizabeth G Nabel; Richard O Cannon; William A Gahl; Wendy J Introne Journal: N Engl J Med Date: 2008-02-07 Impact factor: 91.245
Authors: Seyed Hossein Bassir; Isabelle Chase; Bruce J Paster; Leslie B Gordon; Monica E Kleinman; Mark W Kieran; David M Kim; Andrew Sonis Journal: J Periodontol Date: 2018-06 Impact factor: 6.993
Authors: C M Gordon; R H Cleveland; K Baltrusaitis; J Massaro; R B D'Agostino; M G Liang; B Snyder; M Walters; X Li; D T Braddock; M E Kleinman; M W Kieran; L B Gordon Journal: Bone Date: 2019-05-08 Impact factor: 4.398
Authors: Gianfranco Matrone; Rajarajan A Thandavarayan; Brandon K Walther; Shu Meng; Anahita Mojiri; John P Cooke Journal: Cell Cycle Date: 2019-08-14 Impact factor: 4.534