Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells
AbstractProgeroid 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. View Full-Text
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Harhouri, K.; Navarro, C.; Baquerre, C.; Da Silva, N.; Bartoli, C.; Casey, F.; Mawuse, G.K.; Doubaj, Y.; Lévy, N.; De Sandre-Giovannoli, A. Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells. Cells 2016, 5, 31.
Harhouri K, Navarro C, Baquerre C, Da Silva N, Bartoli C, Casey F, Mawuse GK, Doubaj Y, Lévy N, De Sandre-Giovannoli A. Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells. Cells. 2016; 5(3):31.Chicago/Turabian Style
Harhouri, Karim; Navarro, Claire; Baquerre, Camille; Da Silva, Nathalie; Bartoli, Catherine; Casey, Frank; Mawuse, Guedenon K.; Doubaj, Yassamine; Lévy, Nicolas; De Sandre-Giovannoli, Annachiara. 2016. "Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells." Cells 5, no. 3: 31.
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