title: Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.
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.
authors.affiliation: Department of Anesthesia, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Leslie_Gordon@brown.edu
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Gordon
authors.forename: Monica E
authors.initials: ME
authors.lastname: Kleinman
authors.forename: David T
authors.initials: DT
authors.lastname: Miller
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Anita
authors.initials: A
authors.lastname: Giobbie-Hurder
authors.forename: Marie
authors.initials: M
authors.lastname: Gerhard-Herman
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Smoot
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Gordon
authors.forename: Robert
authors.initials: R
authors.lastname: Cleveland
authors.forename: Brian D
authors.initials: BD
authors.lastname: Snyder
authors.forename: Brian
authors.initials: B
authors.lastname: Fligor
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bishop
authors.forename: Paul
authors.initials: P
authors.lastname: Statkevich
authors.forename: Amy
authors.initials: A
authors.lastname: Regen
authors.forename: Andrew
authors.initials: A
authors.lastname: Sonis
authors.forename: Susan
authors.initials: S
authors.lastname: Riley
authors.forename: Christine
authors.initials: C
authors.lastname: Ploski
authors.forename: Annette
authors.initials: A
authors.lastname: Correia
authors.forename: Nicolle
authors.initials: N
authors.lastname: Quinn
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Ullrich
authors.forename: Ara
authors.initials: A
authors.lastname: Nazarian
authors.forename: Marilyn G
authors.initials: MG
authors.lastname: Liang
authors.forename: Susanna Y
authors.initials: SY
authors.lastname: Huh
authors.forename: Armin
authors.initials: A
authors.lastname: Schwartzman
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
mesh_terms: D000293:Adolescent; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011371:Progeria / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D063177:Pulse Wave Analysis; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced; D015430:Weight Gain / Q000187:drug effects; D003986:Dibenzocycloheptenes
chemical_list: D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D010880:Piperidines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes