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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 ∆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.
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Submitted on : Wednesday, April 18, 2018 - 9:20:50 AM
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Karim Harhouri, Claire L. Navarro, Camille Baquerre, Nathalie da Silva, Catherine Bartoli, et al.. Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells. Cells, MDPI, 2016, 5 (3), pp.31. ⟨10.3390/cells5030031⟩. ⟨hal-01769404⟩



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