Antisense-based progerin downregulation in HGPS-like patients’ cells

Karim Harhouri, Claire Navarro, Camille Baquerre, Nathalie Da Silva, Catherine Bartoli, Frank Casey, Guedenon Koffi Mawuse, Yassamine Doubaj, Nicolas Lévy, Annachiara De Sandre-Giovannoli

Research output: Contribution to journalReview articlepeer-review

25 Citations (Scopus)

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.

Original languageEnglish
Article number31
Pages (from-to)1-15
JournalCells
Volume5
Issue number3
Early online date11 Jul 2016
DOIs
Publication statusE-pub ahead of print - 11 Jul 2016

Bibliographical note

Publisher Copyright:
© 2016 by the authors; licensee MDPI, Basel, Switzerland.

Keywords

  • Antisense oligonucleotides
  • HGPS-like
  • MAD-B
  • Prelamin Δ D35
  • Prelamin Δ D90
  • Progerin

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