Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells

Karim Harhouri (1) , Claire L. Navarro (1) , Camille Baquerre (1) , Nathalie da Silva (1) , Catherine Bartoli (1) , Frank Casey (2) , Guedenon Koffi Mawuse , Yassamine Doubaj (3) , Nicolas Lévy (4, 1) , Annachiara de Sandre-Giovannoli (1, 4)

1 GMGF - Génétique Médicale et Génomique Fonctionnelle
2 Royal Belfast Hospital for Sick Children
3 Institut National d'Hygiène [Maroc]
4 Département de génétique médicale [Hôpital de la Timone - APHM]

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 ∆50 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 (∆35 and ∆90) 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 ∆35, Prelamin A ∆90) 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.

Mots clés: Progerin; antisense oligonucleotides; MAD-B; Prelamin A ∆90; Prelamin A ∆35; HGPS-like

Domaines: Biologie cellulaire

Karim Harhouri, Claire L. Navarro, Camille Baquerre, Nathalie da Silva, Catherine Bartoli, et al.. Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells. Cells, 2016, 5 (3), pp.31. ⟨10.3390/cells5030031⟩. ⟨hal-01769404⟩