title: Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.
abstract: BACKGROUND
  Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications.
  
  
  RESULTS
  We generated Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. Treatment increased mean survival by 1.6 years.
  
  
  CONCLUSIONS
  This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747.
authors.affiliation: From the Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI (L.B.G.); Department of Anesthesia, Division of Critical Care Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA (L.B.G., M.E.K.); Department of Mathematics and Statistics, Boston University, Harvard Clinical Research Institute, Boston, MA (J.M., R.B.D.); Center for Gerontology and Health Care Research, Brown University, Providence, RI (S.E.C., J.B.); Department of Genetics, New York State Institute for Basic Research, Staten Island, NY (W.T.B.); Hematology-Oncology, Boston Children's Hospital, Division of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (M.W.K.). Leslie_Gordon@brown.edu.
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Gordon
authors.affiliation: From the Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI (L.B.G.); Department of Anesthesia, Division of Critical Care Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA (L.B.G., M.E.K.); Department of Mathematics and Statistics, Boston University, Harvard Clinical Research Institute, Boston, MA (J.M., R.B.D.); Center for Gerontology and Health Care Research, Brown University, Providence, RI (S.E.C., J.B.); Department of Genetics, New York State Institute for Basic Research, Staten Island, NY (W.T.B.); Hematology-Oncology, Boston Children's Hospital, Division of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (M.W.K.).
authors.forename: Joe
authors.initials: J
authors.lastname: Massaro
authors.affiliation: From the Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI (L.B.G.); Department of Anesthesia, Division of Critical Care Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA (L.B.G., M.E.K.); Department of Mathematics and Statistics, Boston University, Harvard Clinical Research Institute, Boston, MA (J.M., R.B.D.); Center for Gerontology and Health Care Research, Brown University, Providence, RI (S.E.C., J.B.); Department of Genetics, New York State Institute for Basic Research, Staten Island, NY (W.T.B.); Hematology-Oncology, Boston Children's Hospital, Division of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (M.W.K.).
authors.forename: Ralph B
authors.initials: RB
authors.lastname: D'Agostino
authors.affiliation: From the Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI (L.B.G.); Department of Anesthesia, Division of Critical Care Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA (L.B.G., M.E.K.); Department of Mathematics and Statistics, Boston University, Harvard Clinical Research Institute, Boston, MA (J.M., R.B.D.); Center for Gerontology and Health Care Research, Brown University, Providence, RI (S.E.C., J.B.); Department of Genetics, New York State Institute for Basic Research, Staten Island, NY (W.T.B.); Hematology-Oncology, Boston Children's Hospital, Division of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (M.W.K.).
authors.forename: Susan E
authors.initials: SE
authors.lastname: Campbell
authors.affiliation: From the Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI (L.B.G.); Department of Anesthesia, Division of Critical Care Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA (L.B.G., M.E.K.); Department of Mathematics and Statistics, Boston University, Harvard Clinical Research Institute, Boston, MA (J.M., R.B.D.); Center for Gerontology and Health Care Research, Brown University, Providence, RI (S.E.C., J.B.); Department of Genetics, New York State Institute for Basic Research, Staten Island, NY (W.T.B.); Hematology-Oncology, Boston Children's Hospital, Division of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (M.W.K.).
authors.forename: Joan
authors.initials: J
authors.lastname: Brazier
authors.affiliation: From the Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI (L.B.G.); Department of Anesthesia, Division of Critical Care Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA (L.B.G., M.E.K.); Department of Mathematics and Statistics, Boston University, Harvard Clinical Research Institute, Boston, MA (J.M., R.B.D.); Center for Gerontology and Health Care Research, Brown University, Providence, RI (S.E.C., J.B.); Department of Genetics, New York State Institute for Basic Research, Staten Island, NY (W.T.B.); Hematology-Oncology, Boston Children's Hospital, Division of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (M.W.K.).
authors.forename: W Ted
authors.initials: WT
authors.lastname: Brown
authors.affiliation: From the Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI (L.B.G.); Department of Anesthesia, Division of Critical Care Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA (L.B.G., M.E.K.); Department of Mathematics and Statistics, Boston University, Harvard Clinical Research Institute, Boston, MA (J.M., R.B.D.); Center for Gerontology and Health Care Research, Brown University, Providence, RI (S.E.C., J.B.); Department of Genetics, New York State Institute for Basic Research, Staten Island, NY (W.T.B.); Hematology-Oncology, Boston Children's Hospital, Division of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (M.W.K.).
authors.forename: Monica E
authors.initials: ME
authors.lastname: Kleinman
authors.affiliation: From the Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI (L.B.G.); Department of Anesthesia, Division of Critical Care Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA (L.B.G., M.E.K.); Department of Mathematics and Statistics, Boston University, Harvard Clinical Research Institute, Boston, MA (J.M., R.B.D.); Center for Gerontology and Health Care Research, Brown University, Providence, RI (S.E.C., J.B.); Department of Genetics, New York State Institute for Basic Research, Staten Island, NY (W.T.B.); Hematology-Oncology, Boston Children's Hospital, Division of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (M.W.K.).
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
mesh_terms: D000293:Adolescent; D000328:Adult; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D002423:Cause of Death; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D015331:Cohort Studies; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D034904:Lamin Type A; D008297:Male; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011371:Progeria / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D016016:Proportional Hazards Models; D011498:Protein Precursors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult; D000077211:Zoledronic Acid; D003986:Dibenzocycloheptenes
chemical_list: D019883:Alkyl and Aryl Transferases; D004122:Dimethylallyltranstransferase; D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D034904:Lamin Type A; D009687:Nuclear Proteins; D010880:Piperidines; D017035:Pravastatin; D011498:Protein Precursors; D011725:Pyridines; D000077211:Zoledronic Acid; C090764:prelamin A; C064911:p21(ras) farnesyl-protein transferase; C115354:lonafarnib; D003986:Dibenzocycloheptenes
keywords: Kaplan-Meier estimate; aging; atherosclerosis; lamins; lonafarnib; prenylation; progeria