title: Antisense-Based Progerin Downregulation in HGPS-Like Patients' Cells.
abstract: Progeroid laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670), are premature and accelerated aging diseases caused by defects in nuclear A-type Lamins. Most HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type Lamins. This mutation activates a cryptic splice site leading to the deletion of 50 amino acids at its carboxy-terminal domain, resulting in a truncated and permanently farnesylated Prelamin A called Prelamin A Δ50 or Progerin. Some patients carry other LMNA mutations affecting exon 11 splicing and are named "HGPS-like" patients. They also produce Progerin and/or other truncated Prelamin A isoforms (Δ35 and Δ90) at the transcriptional and/or protein level. The results we present show that morpholino antisense oligonucleotides (AON) prevent pathogenic LMNA splicing, markedly reducing the accumulation of Progerin and/or other truncated Prelamin A isoforms (Prelamin A Δ35, Prelamin A Δ90) in HGPS-like patients' cells. Finally, a patient affected with Mandibuloacral Dysplasia type B (MAD-B, carrying a homozygous mutation in ZMPSTE24, encoding an enzyme involved in Prelamin A maturation, leading to accumulation of wild type farnesylated Prelamin A), was also included in this study. These results provide preclinical proof of principle for the use of a personalized antisense approach in HGPS-like and MAD-B patients, who may therefore be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.
authors.affiliation: Aix Marseille Universit&#233;, INSERM, GMGF UMR_S 910, 13385 Marseille, France. Karim.HARHOURI@univ-amu.fr.
authors.forename: Karim
authors.initials: K
authors.lastname: Harhouri
authors.affiliation: Aix Marseille Universit&#233;, INSERM, GMGF UMR_S 910, 13385 Marseille, France. Claire.NAVARRO@univ-amu.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Navarro
authors.affiliation: Aix Marseille Universit&#233;, INSERM, GMGF UMR_S 910, 13385 Marseille, France. camille.baquerre1@orange.fr.
authors.forename: Camille
authors.initials: C
authors.lastname: Baquerre
authors.affiliation: Aix Marseille Universit&#233;, INSERM, GMGF UMR_S 910, 13385 Marseille, France. Nathalie.DASILVA@univ-amu.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Da Silva
authors.affiliation: Aix Marseille Universit&#233;, INSERM, GMGF UMR_S 910, 13385 Marseille, France. catherine.bartoli@univ-amu.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bartoli
authors.affiliation: Royal Belfast, Pediatric Cardiology, Hospital for Sick Children, Belfast BT9 7AB, Northern Ireland. frank.casey@belfasttrust.hscni.net.
authors.forename: Frank
authors.initials: F
authors.lastname: Casey
authors.affiliation: CHU Sylvanus Olympio de Lom&#233;, Unit&#233; de G&#233;n&#233;tique Humaine, Lom&#233; BP 1515, Togo. julesblack@yahoo.fr.
authors.forename: Guedenon Koffi
authors.initials: GK
authors.lastname: Mawuse
authors.affiliation: D&#233;partement de G&#233;n&#233;tique M&#233;dicale, Institut National d'Hygi&#232;ne, 11400 Rabat, Morocco. y.doubaj@gmail.com.
authors.forename: Yassamine
authors.initials: Y
authors.lastname: Doubaj
authors.affiliation: Aix Marseille Universit&#233;, INSERM, GMGF UMR_S 910, 13385 Marseille, France. nicolas.levy@univ-amu.fr.|Departement of Medical Genetics, la Timone Children's Hospital, APHM, 13385 Marseille, France. nicolas.levy@univ-amu.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.affiliation: Aix Marseille Universit&#233;, INSERM, GMGF UMR_S 910, 13385 Marseille, France. annachiara.desandre-giovannoli@univ-amu.fr.|Departement of Medical Genetics, la Timone Children's Hospital, APHM, 13385 Marseille, France. annachiara.desandre-giovannoli@univ-amu.fr.
authors.forename: Annachiara
authors.initials: A
authors.lastname: De Sandre-Giovannoli
keywords: HGPS-like; MAD-B; Prelamin A Δ35; Prelamin A Δ90; Progerin; antisense oligonucleotides