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  • Oral presentation
  • Open Access

New therapeutic approaches to HGPS based on progerin inhibition

Orphanet Journal of Rare Diseases201510 (Suppl 2) :O8

  • Published:


  • Retinoic Acid
  • Nuclear Shape
  • Damage Marker
  • Surprising Effect
  • Shape Abnormality

Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a de novo heterozygous mutation on LMNA gene that leads to accumulation of progerin, a mutant form of prelamin A. HGPS skin fibroblasts are characterized by multiple nuclear defects: nuclear shape abnormalities chromatin structure alterations, increased DNA damage and cell cycle alterations.

Retinoic acid may modulate LMNA gene transcription, due to the presence of a retinoic acid responsive element (L-RARE) in the LMNA promoter. Based on this knowledge, we investigated if all trans retinoic acid (ATRA) could lower progerin levels in HGPS fibroblasts. We also evaluated the effects of a combined treatment with rapamycin, a drug known to promote autophagy and reduce both farnesylated prelamin A and progerin amount.

We demonstrate a surprising effect of ATRA to repress Lamin A/C gene transcription and we show that the combined treatment with ATRA and rapamycin has a synergistic effect: it dramatically lowers progerin levels, restores both heterochromatin organization and nuclear shape, reduces DNA damage markers and improves cell viability. These promising results could open the way to a new therapeutic approach for HGPS.

Authors’ Affiliations

CNR Institute for Molecular Genetics, Unit of Bologna, Bologna, Italy, Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy