title: Induced pluripotent stem cells reveal functional differences between drugs currently investigated in patients with hutchinson-gilford progeria syndrome.
abstract: Hutchinson-Gilford progeria syndrome is a rare congenital disease characterized by premature aging in children. Identification of the mutation and related molecular mechanisms has rapidly led to independent clinical trials testing different marketed drugs with a preclinically documented impact on those mechanisms. However, the extensive functional effects of those drugs remain essentially unexplored. We have undertaken a systematic comparative study of the three main treatments currently administered or proposed to progeria-affected children, namely, a farnesyltransferase inhibitor, the combination of an aminobisphosphonate and a statin (zoledronate and pravastatin), and the macrolide antibiotic rapamycin. This work was based on the assumption that mesodermal stem cells, which are derived from Hutchinson-Gilford progeria syndrome-induced pluripotent stem cells expressing major defects associated with the disease, may be instrumental to revealing such effects. Whereas all three treatments significantly improved misshapen cell nuclei typically associated with progeria, differences were observed in terms of functional improvement in prelamin A farnesylation, progerin expression, defective cell proliferation, premature osteogenic differentiation, and ATP production. Finally, we have evaluated the effect of the different drug combinations on this cellular model. This study revealed no additional benefit compared with single-drug treatments, whereas a cytostatic effect equivalent to that of a farnesyltransferase inhibitor alone was systematically observed. Altogether, these results reveal the complexity of the modes of action of different drugs, even when they have been selected on the basis of a similar mechanistic hypothesis, and underscore the use of induced pluripotent stem cell derivatives as a critical and powerful tool for standardized, comparative pharmacological studies.
authors.affiliation: INSERM/Université Evry Val d'Essonne 861, and Centre d'Etude des Cellules Souches, Institut for Stem Cell Therapy and Exploration of Monogenic Diseases, Association Française Contre les Myopathies, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, Evry, France; INSERM-Aix-Marseille Université Unité Mixte de Recherche S 910 Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine Timone, Marseille, France; Department of Dermatology and IMETUM, Technische Universitat Munchen, Munich, Germany; AP-HM Département de Génétique Médicale, Hôpital d'Enfants, Timone, Marseille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Blondel
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Jaskowiak
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Egesipe
authors.forename: Amelie
authors.initials: A
authors.lastname: Le Corf
authors.forename: Claire
authors.initials: C
authors.lastname: Navarro
authors.forename: Véronique
authors.initials: V
authors.lastname: Cordette
authors.forename: Cécile
authors.initials: C
authors.lastname: Martinat
authors.forename: Yacine
authors.initials: Y
authors.lastname: Laabi
authors.forename: Karima
authors.initials: K
authors.lastname: Djabali
authors.forename: Annachiara
authors.initials: A
authors.lastname: de Sandre-Giovannoli
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levy
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
authors.forename: Xavier
authors.initials: X
authors.lastname: Nissan
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D007223:Infant; D034904:Lamin Type A; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D017035:Pravastatin / Q000494:pharmacology*; D054876:Prenylation / Q000187:drug effects; D011371:Progeria / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D000924:Anticholesteremic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D000077211:Zoledronic Acid; D017035:Pravastatin
keywords: Aging; Drug development; Mesenchymal stem cells; Pluripotent stem cells; Progeria