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New therapeutic approaches to HGPS based on progerin inhibition

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.

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Correspondence to Camilla Pellegrini.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Pellegrini, C. New therapeutic approaches to HGPS based on progerin inhibition. Orphanet J Rare Dis 10 (Suppl 2), O8 (2015).

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