Skip to main content
  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

  • Home
  • About this Journal
    • Editorial Board
    • General Statistics
    • Circulation Doodle
      • Doodle Gallery
      • Circulation Cover Doodle
        • → Blip the Doodle
    • Information for Advertisers
    • Author Reprints
    • Commercial Reprints
    • Customer Service and Ordering Information
    • Subscribe to AHA Journals
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
      • Recently Published Guidelines
    • Bridging Disciplines
    • Circulation at Major Meetings
    • Special Themed Issues
    • Global Impact of the 2017 ACC/AHA Hypertension Guidelines
    • Circulation Supplements
    • Cardiovascular Case Series
    • ECG Challenge
    • Hospitals of History
      • Brigham and Women's Hospital
      • Hartford Hospital
      • Hospital Santa Maria del Popolo, Naples, Italy
      • Instituto do Coração-INCOR (São Paulo, Brasil)
      • Minneapolis City Hospital
      • Parkland Hospital: Dallas, Texas
      • Pennsylvania Hospital, Philadelphia
      • Pitié-Salpêtrière Hospital
      • Royal Infirmary of Edinburgh, Scotland
      • Tufts Medical Center
      • University of Michigan
      • Uppsala University Hospital
      • Vassar Brothers Medical Center (Poughkeepsie, NY)
      • Wroclaw Medical University
      • Women's College Hospital, Toronto, Canada
      • Henry Ford Hospital, Detroit, Michigan
      • Instituto Nacional de Cardiología Ignacio Chávez – INCICh México City, México
      • Kuang-Tien General Hospital (Taichug, Taiwan)
    • On My Mind
    • Podcast Archive
    • → Subscribe to Circulation on the Run
    • →Circulation FIT Podcast 2018
    • → #FITFAVs
  • Resources
    • Instructions for Authors
      • Accepted Manuscripts
      • Revised Manuscripts
    • → Article Types
    • → General Preparation Instructions
    • → Research Guidelines
    • → How to Submit a Manuscript
    • Journal Policies
    • Permissions and Rights Q&A
    • Submission Sites
    • Circulation CME
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
  • Facebook
  • Twitter

  • My alerts
  • Sign In
  • Join

  • Advanced search

Header Publisher Menu

  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

Circulation

  • My alerts
  • Sign In
  • Join

  • Facebook
  • Twitter
  • Home
  • About this Journal
    • Editorial Board
    • General Statistics
    • Circulation Doodle
    • Information for Advertisers
    • Author Reprints
    • Commercial Reprints
    • Customer Service and Ordering Information
    • Subscribe to AHA Journals
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Bridging Disciplines
    • Circulation at Major Meetings
    • Special Themed Issues
    • Global Impact of the 2017 ACC/AHA Hypertension Guidelines
    • Circulation Supplements
    • Cardiovascular Case Series
    • ECG Challenge
    • Hospitals of History
    • On My Mind
    • Podcast Archive
    • → Subscribe to Circulation on the Run
    • →Circulation FIT Podcast 2018
    • → #FITFAVs
  • Resources
    • Instructions for Authors
    • → Article Types
    • → General Preparation Instructions
    • → Research Guidelines
    • → How to Submit a Manuscript
    • Journal Policies
    • Permissions and Rights Q&A
    • Submission Sites
    • Circulation CME
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
Original Article

Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria SyndromeCLINICAL PERSPECTIVE

Leslie B. Gordon, Joe Massaro, Ralph B. D’Agostino, Susan E. Campbell, Joan Brazier, W. Ted Brown, Monica E. Kleinman, Mark W. Kieran
and and the Progeria Clinical Trials Collaborative
Download PDF
https://doi.org/10.1161/CIRCULATIONAHA.113.008285
Circulation. 2014;130:27-34
Originally published May 2, 2014
Leslie B. Gordon
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.).
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joe Massaro
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.).
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ralph B. D’Agostino
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.).
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susan E. Campbell
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.).
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joan Brazier
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.).
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
W. Ted Brown
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.).
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Monica E. Kleinman
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.).
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark W. Kieran
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.).
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Tables
  • Supplemental Materials
  • Info & Metrics
  • eLetters

Jump to

  • Article
    • Abstract
    • Introduction
    • Methods
    • Results
    • Discussion
    • Appendix
    • Acknowledgments
    • Sources of Funding
    • Disclosures
    • Footnotes
    • References
  • Figures & Tables
  • Supplemental Materials
  • Info & Metrics
  • eLetters
Loading

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.

Methods and 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.

Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747.

  • aging
  • atherosclerosis
  • Kaplan-Meier estimate
  • lamins
  • lonafarnib
  • prenylation
  • progeria

Introduction

Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic autosomal dominant segmental premature aging disease with an incidence of 1 in 4 million.1 Cardiovascular (CV) disease in HGPS is characterized by early and pervasive vascular stiffening, along with later-stage arterial occlusive disease.2–4 These factors are major contributors to an accelerated form of premature atherosclerosis that culminates in early death from heart attack or, less often, stroke.

Editorial see p 4

Clinical Perspective on p 34

The genetic mutations causing HGPS are a series of silent point mutations in the LMNA gene that increase the use of an internal splice site5,6 resulting in translation of the disease-causing abnormal lamin A protein progerin. The normal LMNA gene encodes lamin A, a principal protein of the nuclear lamina, which is a complex molecular interface located between the inner membrane of the nuclear envelope and chromatin (for review, see Broers et al).7 The integrity of the lamina is central to many cellular functions, creating and maintaining structural integrity of the nuclear scaffold, DNA replication, RNA transcription, organization of the nucleus, nuclear pore assembly, chromatin function, cell cycling, and apoptosis.

Disease in HGPS is produced by a dominant-negative mechanism; it is the effect of progerin, not the diminution of lamin A, that causes the disease phenotype.8 Progerin is found in increased concentration in skin and the vascular wall of normal older compared with younger individuals, suggesting a role in normal aging.2,8a Unlike lamin A, progerin lacks the proteolytic cleavage site required for removal of its posttranslationally attached farnesyl moiety.6 Progerin is postulated to remain associated with the inner nuclear membrane, unable to be released for degradation because of persistent farnesylation.9–12

The pathological effects of progerin farnesylation form the central hypothesis underlying treatment protocols using protein farnesylation inhibitors in HGPS. Preclinical studies administering farnesylation inhibitors demonstrated positive effects on both in vitro11,13,14 and murine in vivo15–19 progeria disease models. The preclinical data in support of farnesylation inhibitors was encouraging but complicated. With treatment, HGPS fibroblasts displayed improved nuclear morphology, gene expression, cellular lifespan, and nuclear stiffness.11,13,14,20 However, HGPS fibroblasts also exhibited the potential for alternative prenylation18 and lack of improved sensitivity to mechanical strain20 with farnesyltransferase inhibitor treatment. In vivo, several progeroid mouse models displayed improved phenotype16,18,19,21 and, in some cases, extended lifespan.16,18,21 However, some mouse models display bone or neurological morbidity without overt CV morbidity, and cause of death is undetermined for any mouse model. Given the complicated preclinical results, extended survival in humans could not be assumed and could only be tested with adequate human cohort numbers and treatment duration.

The first human clinical treatment trial for HGPS administered the protein farnesyltransferase inhibitor lonafarnib for 2 years.22 CV and neurovascular results demonstrated evidence for decreased vascular stiffness,22 incidence of stroke, transient ischemic attack, and headache.4 There was also evidence for skeletal and audiologic benefits.22 Improvements occurred in some but not all subjects, and some disease phenotypes were not improved with lonafarnib. Trial duration was inadequate to test influence on survival. The second and currently ongoing trial added 2 additional medications to lonafarnib, also aimed at inhibiting progerin farnesylation. The statin pravastatin inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase, and the bisphosphonate zoledronate inhibits farnesyl–pyrophosphate synthase18; each enzyme functions along the protein prenylation pathway (Figure 1).

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Current HGPS treatment strategies aimed at preventing formation of progerin protein by inhibiting posttranslational farnesylation of preprogerin. Enzymes facilitating each step are italicized. Dashed line indicates that multiple steps in the pathway are not shown. Medications aimed at inhibiting protein farnesylation are circled. ICMT indicates isoprenylcysteine carboxyl methyltransferase.

Along with their influences on protein prenylation, both pravastatin and zoledronate affect disease in subjects without HGPS using mechanisms of action independent of the prenylation pathway. There exists both direct and indirect support for efficacy of these drugs specifically through inhibiting progerin prenylation in HGPS versus alternative mechanisms of action. In vitro, phenotypic improvements in progeroid mouse fibroblasts treated with pravastatin plus zoledronate are completely abolished when cells are allowed to specifically bypass the need for 3-hydroxy-3-methylglutaryl coenzyme A reductase and farnesyl–pyrophosphate synthase.18 In vivo, statins were shown to exert beneficial CV effects through mechanisms distinct from their effect in lowering cholesterol and low-density lipoproteins.23 Additional statin effects were demonstrated in pathways of inflammation, immunomodulation, and thrombosis. However, the usual target pathways of statins do not appear as significant components in the HGPS population. Children with HGPS exhibit normal values for serum total cholesterol and low-density lipoprotein, serum high-sensitivity C-reactive protein,24,25 and arterial intima-media thickness3,25 and demonstrate no overt evidence of endothelial dysfunction. Finally, zoledronate exhibits its major effects by decreasing bone resorption and ultimately improving bone density.26 Although both bone density and skeletal morphology are affected in HGPS,27 fracture rate is normal28 and subjects do not die from bone disease. Thus, influence on HGPS lifespan in humans stemming from zoledronate would likely be attributable to effects outside of the skeletal system.

Assessing change in population survival attributable to treatment necessitates a robust analysis of the untreated HGPS comparison population. Two studies estimated mean survival for this disease group at 13.429 and 12.61 years based mainly on literature searches. Neither included subjects who were living or lost to follow-up (censored data), nor did they generate survival curves. We developed Kaplan–Meier curves and survival estimates for a large untreated HGPS cohort. To assess whether treatment has an influence on survival for children with HGPS, we provide comparisons between this untreated cohort and a treated cohort that received HGPS-specific treatments during clinical trials. A robust comparison required subject matching with regard to age, sex, dates, and other potential confounding factors.

Methods

Inclusion Criteria and Demographics

This project was approved by the Rhode Island Hospital Institutional Review Board. Some data were obtained through a Data Use Agreement between the Progeria Research Foundation, Rhode Island Hospital, and Brown University. The clinical trials were approved by the Boston Children’s Hospital Committee on Clinical Investigation.

Study subjects were identified using the Progeria Research Foundation International Registry (www.progeriaresearch.org), published scientific and news articles, and publicly available databases. Minimum inclusion criteria were as follows: (1) phenotype confirmation by study investigators; (2) living age or age of death; (3) inclusion history in progeria clinical trials (at clinicaltrials.gov) NCT00425607 (lonafarnib monotherapy) and NCT00879034 and NCT00916747 (lonafarnib, zoledronate, and pravastatin combination therapy); and (4) treatment duration. Because of institutional restrictions, 10 subjects with HGPS included in an open-label clinical trial conducted in Marseilles (registered at clinicaltrials.gov as NCT00731016) were unavailable for inclusion in this study (Dr Nicolas Levy, personal communication).

Untreated subjects had not received clinical trial medications within any clinical treatment trial for HGPS. Treated subjects received trial medications for any length of time; treatment initiation and duration varied.

HGPS was defined by clinical phenotype, which is consistent and unique from non-progerin–producing progeroid laminopathies. The main differential diagnosis for HGPS includes mandibulo-acral dysplasia and restrictive dermopathy, which are both attributable to alternative mutations in LMNA. These are both quite distinct in appearance, so there is little possible confusion with the classic HGPS.30 When genotype was known, all positive cases by phenotype contained a progerin-producing mutation in the LMNA gene. Although exclusion of non-progerin–producing laminopathies is reliably accomplished using phenotype in the absence of genotype, there are cases in which the splicing mutation yields very low levels of progerin and a clinically different phenotype that is not categorized as HGPS.31,32 These subjects were not included in the analysis because they are considered non-HGPS by phenotype.

Statistics

Drs Massaro and D’Agostino performed all statistical analyses. Demographic characteristics are presented with counts and percentages and compared between groups using Fisher’s exact test. Untreated patient survival age was estimated by the Kaplan–Meier method. Untreated subjects living as of the start of data analysis and subjects appearing in a published report living at the time of the report but then lost to follow-up (see Table I in the online-only Data Supplement) were censored at the time of their last-known living age. Treatment trial subjects were included as part of the untreated cohort until age of treatment initiation.

Cox proportional hazards regression was used to compare treated and untreated (ie, never treated) groups for survival. To control for potential confounding variables, sex and age matching was performed, and the untreated subject pool included only those born on or after 1991, the year on or after which all treated subjects were born. For every treated patient, all untreated subjects of the same sex who were alive at the age when the treated patient began treatment were identified; from this group of untreated subjects, 1 was randomly selected and used as the matched untreated patient in the analysis. Once an untreated patient was matched to a treated patient, the untreated patient was no longer available for matching. Patient follow-up began at time 0, in which time 0 is set to the age of treatment initiation for the treated patient in the matched pair. Supportive analyses were performed in which all subjects were followed from birth and placed at risk at the age of treatment initiation. Age, sex and continent of residency were included as covariates in these Cox models.

Treated and untreated subjects born on or after 1991 were compared using treatment (yes/no) as a time-dependent covariate, in which all treated subjects were considered untreated until time of treatment initiation and in which sex and continent of residence were included as covariates. For at least the first 2 years of age, all subjects are untreated, yielding 0 treated subjects during this timeframe and 8 treated subjects through approximately ages 0 to 4 years. In other words, although all subjects (treated and untreated) are theoretically placed at risk for mortality at birth in the time-dependent analysis, in reality, the treated subjects are only truly at risk at the age they began treatment, which was at least 2 years of age for all treated subjects, theoretically yielding a survival advantage in at least the first 2 years of life for the treated patients over the untreated patients. The survival advantage was not large, because only 1 untreated patient born after 1991 died before 2 years of age; nevertheless, for this potential bias in favor of the treated group, we considered the time-dependent analysis as supportive.

Hazard ratios (HRs) and their 2-sided 95% confidence intervals (CIs) for mortality in treated versus untreated were calculated. Sensitivity analyses were conducted by removing or censoring subjects with various confounding variables listed in Results.

Estimated extension in mean survival with treated versus untreated subjects was calculated by comparing areas under the treated and untreated Kaplan–Meier curves for the matched sample set.

Statistical analysis was performed using SAS version 9.3 and STATA version 12. P values are 2 sided and deemed significant at 0.05.

Results

Patient Characteristics

Overall, 161 untreated subjects and 43 treated subjects (100% of HGPS clinical trial subjects) were eligible for analysis. Subject sources are detailed in the online-only Data Supplement Appendix. For matched analysis of untreated versus treated cohorts, sex (P=1.00), continent (P=0.39), and known mutation subgroups (P=0.16) were similar (Table).

View this table:
  • View inline
  • View popup
Table.

Patient Characteristics

Cause of death was identified for 50 of the 102 deceased untreated subjects and was attributed to CV failure (n=40; 80%), head injury or trauma (n=5; 10%), stroke (n=2; 4%), respiratory infection superimposed on CV disease (n=2; 4%), and complications from anesthesia during surgery (n=1; 2%). Similarly, cause of death in the 5 deceased trial participants was CV failure (n=3; 60%), head injury (n=1; 20%), and stroke (n=1; 20%).

Trial Medication Side Effects

Notable lonafarnib monotherapy-related side effects included the following: (1) mild diarrhea; (2) fatigue; (3) nausea; (4) vomiting; (5) anorexia; (6) transiently elevated aspartate aminotransferase and alanine aminotransferase; and (7) depressed serum hemoglobin. All generally improved with time and are detailed by Gordon et al.22 Because the combination trial is ongoing, a detailed account of toxicities is not available. However, to date, the most notable side effects include zoledronate-related postinfusion flu-like symptoms,33 pravastatin-induced transient muscle discomfort, and mildly elevated creatine phosphokinase.34

Survival Analysis for Untreated Group

Analysis of the full untreated cohort (n=204), including treatment trial participants censored at the time of treatment initiation, provided a Kaplan–Meier survival curve for HGPS (Figure 2A). Mean and median survival were 14.6 and 14.5 years, respectively.

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Kaplan–Meier survival estimates for untreated and treated HGPS cohorts. The number of patients at risk are presented below the x axis. Numbers in parentheses are number of deaths during that time interval. A, Untreated cohort. Treated subjects were included but censored at age of treatment initiation. Mean and median survival were 14.6 and 14.5 years, respectively. B, Kaplan–Meier survival estimates comparing untreated (solid line) with treated (dashed line) cohorts using matched analysis (age-adjusted P<0.001) in which time 0 on the x axis (ie, beginning of the patient being at risk) is defined for each matched pair as the age of treatment initiation for the treated patient in the matched pair. C, Kaplan–Meier survival estimates comparing untreated (solid line) with treated (dashed line) cohorts using matched analysis (unadjusted P<0.001) in which time 0 on the x axis (ie, beginning of the patient follow-up) is defined as patient birth and the subject becomes at risk at the age of treatment initiation for the treated patient in the matched pair.

Subgroup comparisons were conducted, with no significance found (see Table II in the online-only Data Supplement). These included male versus female and known versus unknown genotype. The possibility that general medical advances over time would improve survival for more recent subjects was addressed by comparing subjects born before 1986 with those born on or after 1986 (~50% of subjects). The possibility that healthier subjects would be removed from the untreated cohort as they enrolled in treatment trials was addressed by censoring the entire patient cohort at the clinical trial initiation date, May 2007.

For use in future comparison studies by other investigators, data elements for all subjects are provided (see Tables I and III through V in the online-only Data Supplement).

Association Between Farnesylation Inhibitors and Survival

There were 5 of 43 (11.6%) deaths in the treated group and 21 of 43 (48.8%) deaths in the matched untreated group. Median follow-up from time of treatment initiation in both treatment groups (untreated subjects matched to treated subjects) is 5.3 years (quartiles of 3.3–5.5 years).

Kaplan–Meier estimates demonstrated increased mortality for the untreated cohort over the treated cohort when follow-up begins at age of treatment initiation for the treated patient in the matched pair (age- and sex-adjusted P<0.001; Figure 2B). Age-, sex-, and continent-adjusted HR for mortality of treated subjects in the matched analysis was 0.15 and therefore positively associated with survival (95% CI, 0.04–0.43). Kaplan–Meier estimates similarly demonstrated increased mortality for untreated when follow-up begins at birth with subjects placed at risk at the age of treatment initiation for the treated patient in the matched pair (P<0.001; Figure 2C). Time-dependent analyses on patients born after 1991 yielded increased survival with P=0.017 and sex- and continent-adjusted HR=0.28 (95% CI, 0.10–0.79; Figure 3).

Figure 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3.

Hazard ratios (HRs) comparing untreated with treated cohorts using matched analyses and time-dependent analysis for patients born on or after 1991. HRs and P values were generated from Cox proportional hazards regression and adjusted for sex and continent. *For each matched pair, follow-up begins at time 0 defined as the age of treatment initiation for the treated patient in the matched pair; HR and P value further adjusted for age at risk. **For each matched pair, follow-up begins at birth, and the patient is placed at risk at the age of treatment initiation for the treated patient in the matched pair; HR and P value further adjusted for age at risk.

During the first 6 years after treatment initiation for the treated patient in the matched pair, extension in mean survival with treatment was 1.6 years, with a 95% CI of 0.8 to 2.4 years (P<0.001). There was a 33% increase in Kaplan–Meier area under the curve for treated versus untreated. To account for potential confounding variables within comparisons between untreated and treated cohorts, a sensitivity analysis that either excluded or censored specific subjects was conducted as follows. Two prospective subjects could not enroll because of health issues and were omitted from the untreated group. Five trial subjects taking recombinant growth hormone were omitted from the treated group. Clinical trial subjects did not generally receive clinical care at the trial hospital site, because clinical care was the responsibility of the subjects’ home physicians. However, 1 trial patient received clinical care from the clinical trial group starting at age 18.4 years because of urgent clinical need while at the trial site. This subject returned home after care was completed and subsequently passed away at home at age 20.3 years. To account for this trial site clinical care, sensitivity analysis was performed where this patient was censored at age 18.4. Other than these variables, there were no known differences between subjects who enrolled and those who did not enroll in the clinical trials. Results of this sensitivity analysis were similar to those described above.

Discussion

This study demonstrates that, without treatment, HGPS survival distribution is stable and independent of sex or medical advances, because males compared with females, as well as pre-1986 compared with post-1986 Kaplan–Meier curves, were similar. This implies that the progerin-associated morbidity is the overriding factor in survival. The quality and quantity of data for the reference population are key to current and future success in assessing changes in survival. Given that the estimated prevalence of HGPS is currently 1 in 18 million,35 this study captured a significant portion of the population.

This study is the first to demonstrate a positive effect of any treatment on estimated survival in HGPS. Results were consistent across 8 different possible confounding variables (sex, continent of origin, mutation status, birth year, medical advances, growth hormone treatment, failing health, trial site clinical treatment), and various analytic methods, strengthening our assertion that farnesylation inhibitors positively influenced patient survival. Because these children die from sequelae of a pervasive premature, progressive form of atherosclerosis, we speculate that extended survival is attributable to CV and possibly cerebrovascular benefits. This premise is supported by secondary outcomes showing evidence for decreased pulse wave velocity, carotid artery wall echodensity, and incidence of stroke, headache, and seizures in subjects treated with lonafarnib monotherapy.4,22

Because each treatment trial was sequential and of relatively short duration (2 years on lonafarnib monotherapy and 3.5 years on combination therapy), the analysis did not distinguish individual drug influences on longevity. Because lonafarnib is the drug to which all subjects have been exposed and for the longest period of time in most instances, we speculate that this drug is primarily responsible for the estimated life extension. This speculation takes into account the CV and neurovascular systems being responsible for most deaths and the improvements seen in some CV and neurovascular properties with lonafarnib treatment. To evaluate further whether addition of zoledronate and pravastatin may be beneficial, neutral, or harmful to morbidity and mortality, it will be crucial to compare CV and other clinical changes with combination therapy with those of lonafarnib monotherapy, once the combination therapy trial is completed.

In the treated group 5 of 43 subjects died compared with 21 of 43 in the untreated matched comparison group, both with median follow-up of 5.3 years. Treatment group inclusion was independent of duration of treatment, age, or stage of disease at treatment initiation. The HR of 0.13 indicates that, given a specific point in time, subjects with HGPS receiving farnesylation inhibitors demonstrated an 80% reduction in risk of death compared with untreated subjects. Interpretation of this effect is complicated by the longitudinal nature of the Kaplan–Meier curve and variable treatment times for different subjects. The estimated 1.6 years of extended survival may be conservative because many subjects started treatment late in their disease course and may potentially benefit from earlier initiation of farnesyltransferase inhibitor therapy and given that most subjects were still living at the time of analysis because of the short follow-up time. This is a statistical estimate; it will take ~6 years until a true extension in mean survival can be determined from actual treated cohort age.

This study was limited by the use of an external untreated control group. For HGPS and other ultrarare, fatal pediatric diseases with no known treatments, only single-arm clinical trials have been conducted to date and are therefore the sole source of data to demonstrate safety and efficacy of any potential new treatment. We attempted to address this issue by using a matching statistical analysis and integrating potential confounding variables.

There are no previously established life-extending treatments for HGPS. Farnesylation inhibitors are clearly not curative, because many features of disease persist despite treatment.22 However, evidence suggesting that survival may be improved by these medications offers a first step in recognizing that treatments aimed at further reducing progerin could thwart its fatal effects.

Appendix

Drs Gordon, Massaro, D’Agostino, Campbell, Brazier, Kleinman, and Kieran are Progeria Clinical Trials Collaborative members. Additional participating Progeria Clinical Trials Collaborative investigators include the following (in alphabetical order): W. Robert Bishop, PhD (Merck Research Labs, Kenilworth, NJ), Robert H. Cleveland, MD (Department of Radiology, Boston Children’s Hospital and Harvard Medical School, Boston, MA), Marie Gerhard-Herman, MD (Department of Cardiology, Brigham and Women’s Hospital, Boston, MA), Catherine M. Gordon, MD, MSc (Department of Pediatrics, Hasbro Children’s Hospital and Warren Alpert Medical School of Brown University, Providence, RI), Susanna Y. Huh, MD, MPH (Division of Gastroenterology and Nutrition, Boston Children’s Hospital and Harvard Medical School), Marilyn Liang, MD, Division of Dermatology, Boston Children’s Hospital and Harvard Medical School, David T. Miller, MD, PhD (Division of Genetics and Laboratory Medicine, Boston Children’s Hospital and Harvard Medical School), Marsha Moses, PhD (Department of Surgery, Boston Children’s Hospital and Harvard Medical School), Ara Nazarian, PhD (Center for Advanced Orthopedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA), Susan Riley (Department of Physical Therapy, Boston Children’s Hospital), V. Michelle Silvera, MD (Department of Radiology, Boston Children’s Hospital and Harvard Medical School), Leslie Smoot, MD (Department of Cardiology, Boston Children’s Hospital and Harvard Medical School), Brian D. Snyder, MD, PhD (Department of Orthopedics, Boston Children’s Hospital and Harvard Medical School), and Nicole J. Ullrich, MD, PhD (Department of Neurology, Boston Children’s Hospital and Harvard Medical School).

Acknowledgments

We are extremely grateful to the children with progeria and their families for participation in this study. We thank Erin Bettencourt and Lynne MacKenzie for assistance with data collection at The Progeria Research Foundation, Dr Alan Hubbard for initial project discussions, The Sunshine Foundation, Dr Nicolas Levy, Marjet Stamsnijder, and Dr Raoul Hennekam for patient communications, Boston team members Annette Corriea, Dr Brian Fligor, Anita Giobbie-Hurder, Dr Marilyn G. Liang, Dr Donna Neuberg, Christine Ploski, Nicolle Quinn, Dr Amy Regen, Susan Riley, and Dr Andrew Sonis, and Merck members Drs Paul Statkevich and David Harris.

Sources of Funding

The Natural History Study was supported by the Progeria Research Foundation. Progeria Clinical Trials were supported by Progeria Research Foundation grants PRFCLIN2007-01, PRFCLIN2009-02, and PRFCLIN2009-03, National Heart, Lung, and Blood Institute grant 1RC2HL101631-0, and National Institutes of Health grants MO1-RR02172 (to the Boston Children’s Hospital General Clinical Research Center) and UL1 RR025758-01 (to the Harvard Catalyst Clinical and Translational Science Center).

Disclosures

Dr Gordon is the parent of a child who participated in the study. The other authors report no conflicts.

Footnotes

  • Guest editor for this article was Ryuichi Morishita, MD, PhD.

  • The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.113.008285/-/DC1.

  • Received December 19, 2013.
  • Accepted April 15, 2014.
  • © 2014 American Heart Association, Inc.

References

  1. 1.↵
    1. Hennekam RC
    . Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A. 2006;140:2603–2624.
    OpenUrlPubMed
  2. 2.↵
    1. Olive M,
    2. Harten I,
    3. Mitchell R,
    4. Beers JK,
    5. Djabali K,
    6. Cao K,
    7. Erdos MR,
    8. Blair C,
    9. Funke B,
    10. Smoot L,
    11. Gerhard-Herman M,
    12. Machan JT,
    13. Kutys R,
    14. Virmani R,
    15. Collins FS,
    16. Wight TN,
    17. Nabel EG,
    18. Gordon LB
    . Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol. 2010;30:2301–2309.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Gerhard-Herman M,
    2. Smoot LB,
    3. Wake N,
    4. Kieran MW,
    5. Kleinman ME,
    6. Miller DT,
    7. Schwartzman A,
    8. Giobbie-Hurder A,
    9. Neuberg D,
    10. Gordon LB
    . Mechanisms of premature vascular aging in children with Hutchinson-Gilford progeria syndrome. Hypertension. 2012;59:92–97.
    OpenUrlCrossRef
  4. 4.↵
    1. Ullrich NJ,
    2. Kieran MW,
    3. Miller DT,
    4. Gordon LB,
    5. Cho YJ,
    6. Silvera VM,
    7. Giobbie-Hurder A,
    8. Neuberg D,
    9. Kleinman ME
    . Neurologic features of Hutchinson-Gilford progeria syndrome after lonafarnib treatment. Neurology. 2013;81:427–430.
    OpenUrlCrossRef
  5. 5.↵
    1. De Sandre-Giovannoli A,
    2. Bernard R,
    3. Cau P,
    4. Navarro C,
    5. Amiel J,
    6. Boccaccio I,
    7. Lyonnet S,
    8. Stewart CL,
    9. Munnich A,
    10. Le Merrer M,
    11. Lévy N
    . Lamin a truncation in Hutchinson-Gilford progeria. Science. 2003;300:2055.
    OpenUrlFREE Full Text
  6. 6.↵
    1. Eriksson M,
    2. Brown WT,
    3. Gordon LB,
    4. Glynn MW,
    5. Singer J,
    6. Scott L,
    7. Erdos MR,
    8. Robbins CM,
    9. Moses TY,
    10. Berglund P,
    11. Dutra A,
    12. Pak E,
    13. Durkin S,
    14. Csoka AB,
    15. Boehnke M,
    16. Glover TW,
    17. Collins FS
    . Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423:293–298.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Broers JL,
    2. Ramaekers FC,
    3. Bonne G,
    4. Yaou RB,
    5. Hutchison CJ
    . Nuclear lamins: laminopathies and their role in premature ageing. Physiol Rev. 2006;86:967–1008.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Fong LG,
    2. Ng JK,
    3. Lammerding J,
    4. Vickers TA,
    5. Meta M,
    6. Coté N,
    7. Gavino B,
    8. Qiao X,
    9. Chang SY,
    10. Young SR,
    11. Yang SH,
    12. Stewart CL,
    13. Lee RT,
    14. Bennett CF,
    15. Bergo MO,
    16. Young SG
    . Prelamin A and lamin A appear to be dispensable in the nuclear lamina. J Clin Invest. 2006;116:743–752.
    OpenUrlCrossRefPubMed
  9. 8a.
    1. McClintock D,
    2. Ratner D,
    3. Lokuge M,
    4. Owens DM,
    5. Gordon L,
    6. Collins FS,
    7. Djabali K
    . The mutant form of lamin a that causes hutchinson-gilford progeria is a biomarker of cellular aging in human skin. PloS one. 2007;2:1–9.
    OpenUrl
  10. 9.↵
    1. Goldman RD,
    2. Shumaker DK,
    3. Erdos MR,
    4. Eriksson M,
    5. Goldman AE,
    6. Gordon LB,
    7. Gruenbaum Y,
    8. Khuon S,
    9. Mendez M,
    10. Varga R,
    11. Collins FS
    . Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2004;101:8963–8968.
    OpenUrlAbstract/FREE Full Text
  11. 10.↵
    1. Scaffidi P,
    2. Misteli T
    . Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat Med. 2005;11:440–445.
    OpenUrlCrossRefPubMed
  12. 11.↵
    1. Capell BC,
    2. Erdos MR,
    3. Madigan JP,
    4. Fiordalisi JJ,
    5. Varga R,
    6. Conneely KN,
    7. Gordon LB,
    8. Der CJ,
    9. Cox AD,
    10. Collins FS
    . Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2005;102:12879–12884.
    OpenUrlAbstract/FREE Full Text
  13. 12.↵
    1. Scaffidi P,
    2. Misteli T
    . Lamin A-dependent nuclear defects in human aging. Science. 2006;312:1059–1063.
    OpenUrlAbstract/FREE Full Text
  14. 13.↵
    1. Glynn MW,
    2. Glover TW
    . Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum Mol Genet. 2005;14:2959–2969.
    OpenUrlAbstract/FREE Full Text
  15. 14.↵
    1. Toth JI,
    2. Yang SH,
    3. Qiao X,
    4. Beigneux AP,
    5. Gelb MH,
    6. Moulson CL,
    7. Miner JH,
    8. Young SG,
    9. Fong LG
    . Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proc Natl Acad Sci U S A. 2005;102:12873–12878.
    OpenUrlAbstract/FREE Full Text
  16. 15.↵
    1. Yang SH,
    2. Meta M,
    3. Qiao X,
    4. Frost D,
    5. Bauch J,
    6. Coffinier C,
    7. Majumdar S,
    8. Bergo MO,
    9. Young SG,
    10. Fong LG
    . A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. J Clin Invest. 2006;116:2115–2121.
    OpenUrlCrossRefPubMed
  17. 16.↵
    1. Fong LG,
    2. Frost D,
    3. Meta M,
    4. Qiao X,
    5. Yang SH,
    6. Coffinier C,
    7. Young SG
    . A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science. 2006;311:1621–1623.
    OpenUrlAbstract/FREE Full Text
  18. 17.↵
    1. Yang SH,
    2. Qiao X,
    3. Fong LG,
    4. Young SG
    . Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation. Biochim Biophys Acta. 2008;1781:36–39.
    OpenUrlCrossRefPubMed
  19. 18.↵
    1. Varela I,
    2. Pereira S,
    3. Ugalde AP,
    4. Navarro CL,
    5. Suárez MF,
    6. Cau P,
    7. Cadiñanos J,
    8. Osorio FG,
    9. Foray N,
    10. Cobo J,
    11. de Carlos F,
    12. Lévy N,
    13. Freije JM,
    14. López-Otín C
    . Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med. 2008;14:767–772.
    OpenUrlCrossRefPubMed
  20. 19.↵
    1. Capell BC,
    2. Olive M,
    3. Erdos MR,
    4. Cao K,
    5. Faddah DA,
    6. Tavarez UL,
    7. Conneely KN,
    8. Qu X,
    9. San H,
    10. Ganesh SK,
    11. Chen X,
    12. Avallone H,
    13. Kolodgie FD,
    14. Virmani R,
    15. Nabel EG,
    16. Collins FS
    . A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model. Proc Natl Acad Sci U S A. 2008;105:15902–15907.
    OpenUrlAbstract/FREE Full Text
  21. 20.↵
    1. Verstraeten V,
    2. Ji J,
    3. Cummings K,
    4. Lee R,
    5. Lammerding J
    . Hutchinson-gilford progeria cells: Effects of farnesyltransferase inhibitors. Aging Cell. 2008;7:383–393.
    OpenUrlCrossRefPubMed
  22. 21.↵
    1. Yang SH,
    2. Bergo MO,
    3. Toth JI,
    4. Qiao X,
    5. Hu Y,
    6. Sandoval S,
    7. Meta M,
    8. Bendale P,
    9. Gelb MH,
    10. Young SG,
    11. Fong LG
    . Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation. Proc Natl Acad Sci U S A. 2005;102:10291–10296.
    OpenUrlAbstract/FREE Full Text
  23. 22.↵
    1. Gordon LB,
    2. Kleinman ME,
    3. Miller DT,
    4. Neuberg DS,
    5. Giobbie-Hurder A,
    6. Gerhard-Herman M,
    7. Smoot LB,
    8. Gordon CM,
    9. Cleveland R,
    10. Snyder BD,
    11. Fligor B,
    12. Bishop WR,
    13. Statkevich P,
    14. Regen A,
    15. Sonis A,
    16. Riley S,
    17. Ploski C,
    18. Correia A,
    19. Quinn N,
    20. Ullrich NJ,
    21. Nazarian A,
    22. Liang MG,
    23. Huh SY,
    24. Schwartzman A,
    25. Kieran MW
    . Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2012;109:16666–16671.
    OpenUrlAbstract/FREE Full Text
  24. 23.↵
    1. Halcox JP,
    2. Deanfield JE
    . Beyond the laboratory: clinical implications for statin pleiotropy. Circulation. 2004;109(21 Suppl 1):II42–II48.
    OpenUrlCrossRefPubMed
  25. 24.↵
    1. Gordon LB,
    2. Harten IA,
    3. Patti ME,
    4. Lichtenstein AH
    . Reduced adiponectin and HDL cholesterol without elevated C-reactive protein: clues to the biology of premature atherosclerosis in Hutchinson-Gilford Progeria Syndrome. J Pediatr. 2005;146:336–341.
    OpenUrlCrossRefPubMed
  26. 25.↵
    1. Merideth MA,
    2. Gordon L,
    3. Clauss S,
    4. Sachdev V,
    5. Smith A,
    6. Perry M,
    7. Brewer C,
    8. Zalewski C,
    9. Kim H,
    10. Solomon B,
    11. Brooks B,
    12. Gerber L,
    13. Turner M,
    14. Domingo DL,
    15. Hart TC,
    16. Graf J,
    17. Reynolds J,
    18. Gropman A,
    19. Yanovski J,
    20. Gerhard-Herman M,
    21. Collins FS,
    22. Nabel EG,
    23. Cannon R,
    24. Gahl WA,
    25. Introne WJ
    . Phenotype and course of hutchinson-gilford progeria syndrome. New Engl J Med. 2008;358:592–604.
    OpenUrlCrossRefPubMed
  27. 26.↵
    1. Räkel A,
    2. Boucher A,
    3. Ste-Marie LG
    . Role of zoledronic acid in the prevention and treatment of osteoporosis. Clin Interv Aging. 2011;6:89–99.
    OpenUrlPubMed
  28. 27.↵
    1. Gordon CM,
    2. Gordon LB,
    3. Snyder BD,
    4. Nazarian A,
    5. Quinn N,
    6. Huh S,
    7. Giobbie-Hurder A,
    8. Neuberg D,
    9. Cleveland R,
    10. Kleinman M,
    11. Miller DT,
    12. Kieran MW
    . Hutchinson-Gilford progeria is a skeletal dysplasia. J Bone Miner Res. 2011;26:1670–1679.
    OpenUrlCrossRefPubMed
  29. 28.↵
    1. Gordon LB,
    2. McCarten KM,
    3. Giobbie-Hurder A,
    4. Machan JT,
    5. Campbell SE,
    6. Berns SD,
    7. Kieran MW
    . Disease progression in Hutchinson-Gilford progeria syndrome: impact on growth and development. Pediatrics. 2007;120:824–833.
    OpenUrlAbstract/FREE Full Text
  30. 29.↵
    1. DeBusk FL
    . The Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the literature. J Pediatr. 1972;80:697–724.
    OpenUrlCrossRefPubMed
  31. 30.↵
    1. Hennekam RCM,
    2. Krantz ID,
    3. Allanson JE.
    Gorlin’s Syndromes of the Head and Neck. 5th ed. New York: Oxford University Press; 2010:447.
  32. 31.↵
    1. Shalev SA,
    2. De Sandre-Giovannoli A,
    3. Shani AA,
    4. Levy N
    . An association of Hutchinson-Gilford progeria and malignancy. Am J Med Genet A. 2007;143A:1821–1826.
    OpenUrl
  33. 32.↵
    1. Hisama FM,
    2. Lessel D,
    3. Leistritz D,
    4. Friedrich K,
    5. McBride KL,
    6. Pastore MT,
    7. Gottesman GS,
    8. Saha B,
    9. Martin GM,
    10. Kubisch C,
    11. Oshima J
    . Coronary artery disease in a Werner syndrome-like form of progeria characterized by low levels of progerin, a splice variant of lamin A. Am J Med Genet A. 2011;155A:3002–3006.
    OpenUrlCrossRef
  34. 33.↵
    1. Munns CF,
    2. Rajab MH,
    3. Hong J,
    4. Briody J,
    5. Högler W,
    6. McQuade M,
    7. Little DG,
    8. Cowell CT
    . Acute phase response and mineral status following low dose intravenous zoledronic acid in children. Bone. 2007;41:366–370.
    OpenUrlCrossRefPubMed
  35. 34.↵
    1. Pfeffer MA,
    2. Keech A,
    3. Sacks FM,
    4. Cobbe SM,
    5. Tonkin A,
    6. Byington RP,
    7. Davis BR,
    8. Friedman CP,
    9. Braunwald E
    . Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project. Circulation. 2002;105:2341–2346.
    OpenUrlAbstract/FREE Full Text
  36. 35.↵
    1. Gordon LB
    . PRF by the numbers. 2013; HGPS Information Resource. Available at: http://www.progeriaresearch.org/prf-by-the-numbers.html. Accessed April 2, 2014.

CLINICAL PERSPECTIVE

Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease uniformly resulting in early death from heart attack or stroke. There is no approved treatment and no proven strategy for extending lifespan. Recently, several clinical trials administered drugs that interfere with protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. We conducted a study to ask whether estimated lifespan is extended as a result of 1 or more these treatments. We first established a robust analysis of an untreated Hutchinson-Gilford progeria syndrome population to generate Kaplan–Meier survival curves that can be used henceforth for treatment comparisons. Survival was distributed normally; the mean was 14.6 years. We then conducted a series of survival comparisons with the treated populations, accounting for age, sex, and 8 additional possible confounding variables. The hazard ratio was 0.13 (95% confidence interval, 0.04–0.37; P<0.001), with median follow-up of 5.3 years. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. The analysis did not distinguish individual drug influences on longevity. The study provides the first evidence of treatments influencing survival for this fatal disease. Because lonafarnib is the drug to which all treated subjects have been exposed and for the longest period of time in most instances, we speculate that this drug is responsible for the largest proportion of estimated life extension. Farnesylation inhibitors are clearly not curative, because most features, including cardiovascular disease, persist despite treatment. However, this study offers a first step in recognizing that treatments aimed at further reducing progerin could thwart its fatal effects.

View Abstract
Back to top
Previous ArticleNext Article

This Issue

Circulation
July 1, 2014, Volume 130, Issue 1
  • Table of Contents
Previous ArticleNext Article

Jump to

  • Article
    • Abstract
    • Introduction
    • Methods
    • Results
    • Discussion
    • Appendix
    • Acknowledgments
    • Sources of Funding
    • Disclosures
    • Footnotes
    • References
  • Figures & Tables
  • Supplemental Materials
  • Info & Metrics
  • eLetters

Article Tools

  • Print
  • Citation Tools
    Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria SyndromeCLINICAL PERSPECTIVE
    Leslie B. Gordon, Joe Massaro, Ralph B. D’Agostino, Susan E. Campbell, Joan Brazier, W. Ted Brown, Monica E. Kleinman and Mark W. Kieran and the Progeria Clinical Trials Collaborative
    Circulation. 2014;130:27-34, originally published May 2, 2014
    https://doi.org/10.1161/CIRCULATIONAHA.113.008285

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
  •  Download Powerpoint
  • Article Alerts
    Log in to Email Alerts with your email address.
  • Save to my folders

Share this Article

  • Email

    Thank you for your interest in spreading the word on Circulation.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria SyndromeCLINICAL PERSPECTIVE
    (Your Name) has sent you a message from Circulation
    (Your Name) thought you would like to see the Circulation web site.
  • Share on Social Media
    Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria SyndromeCLINICAL PERSPECTIVE
    Leslie B. Gordon, Joe Massaro, Ralph B. D’Agostino, Susan E. Campbell, Joan Brazier, W. Ted Brown, Monica E. Kleinman and Mark W. Kieran and the Progeria Clinical Trials Collaborative
    Circulation. 2014;130:27-34, originally published May 2, 2014
    https://doi.org/10.1161/CIRCULATIONAHA.113.008285
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects

  • Basic, Translational, and Clinical Research
    • Mechanisms
  • Intervention, Surgery, Transplantation
    • Treatment
  • Genetics
    • Genetics
  • Epidemiology, Lifestyle, and Prevention
    • Epidemiology

Circulation

  • About Circulation
  • Instructions for Authors
  • Circulation CME
  • Statements and Guidelines
  • Meeting Abstracts
  • Permissions
  • Journal Policies
  • Email Alerts
  • Open Access Information
  • AHA Journals RSS
  • AHA Newsroom

Editorial Office Address:
200 Fifth Avenue, Suite 1020
Waltham, MA 02451
email: circ@circulationjournal.org
 

Information for:
  • Advertisers
  • Subscribers
  • Subscriber Help
  • Institutions / Librarians
  • Institutional Subscriptions FAQ
  • International Users
American Heart Association Learn and Live
National Center
7272 Greenville Ave.
Dallas, TX 75231

Customer Service

  • 1-800-AHA-USA-1
  • 1-800-242-8721
  • Local Info
  • Contact Us

About Us

Our mission is to build healthier lives, free of cardiovascular diseases and stroke. That single purpose drives all we do. The need for our work is beyond question. Find Out More about the American Heart Association

  • Careers
  • SHOP
  • Latest Heart and Stroke News
  • AHA/ASA Media Newsroom

Our Sites

  • American Heart Association
  • American Stroke Association
  • For Professionals
  • More Sites

Take Action

  • Advocate
  • Donate
  • Planned Giving
  • Volunteer

Online Communities

  • AFib Support
  • Garden Community
  • Patient Support Network
  • Professional Online Network

Follow Us:

  • Follow Circulation on Twitter
  • Visit Circulation on Facebook
  • Follow Circulation on Google Plus
  • Follow Circulation on Instagram
  • Follow Circulation on Pinterest
  • Follow Circulation on YouTube
  • Rss Feeds
  • Privacy Policy
  • Copyright
  • Ethics Policy
  • Conflict of Interest Policy
  • Linking Policy
  • Diversity
  • Careers

©2018 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. The American Heart Association is a qualified 501(c)(3) tax-exempt organization.
*Red Dress™ DHHS, Go Red™ AHA; National Wear Red Day ® is a registered trademark.

  • PUTTING PATIENTS FIRST National Health Council Standards of Excellence Certification Program
  • BBB Accredited Charity
  • Comodo Secured