tretinoin and Progeria

Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder that causes systemic accelerated aging in children. Thanks to the pluripotency and self-renewal properties of induced pluripotent stem cells (iPSC), HGPS iPSC-based modeling opens up the possibility of access to different relevant cell types for pharmacological approaches. In this study, 2800 small molecules were explored using high-throughput screening, looking for compounds that could potentially reduce the alkaline phosphatase activity of HGPS mesenchymal stem cells (MSCs) committed into osteogenic differentiation. Results revealed seven compounds that normalized the osteogenic differentiation process and, among these, all-trans retinoic acid and 13-cis-retinoic acid, that also decreased progerin expression. This study highlights the potential of high-throughput drug screening using HGPS iPS-derived cells, in order to find therapeutic compounds for HGPS and, potentially, for other aging-related disorders.

Topics: Aging, Premature; Alkaline Phosphatase; Cell Differentiation; Child; Gene Expression Regulation; Guided Tissue Regeneration; High-Throughput Screening Assays; Humans; Induced Pluripotent Stem Cells; Isotretinoin; Lamin Type A; Mesenchymal Stem Cells; Osteogenesis; Progeria; Tretinoin

Hutchinson Gilford progeria syndrome is a fatal disorder characterized by accelerated aging, bone resorption and atherosclerosis, caused by a LMNA mutation which produces progerin, a mutant lamin A precursor. Progeria cells display progerin and prelamin A nuclear accumulation, altered histone methylation pattern, heterochromatin loss, increased DNA damage and cell cycle alterations. Since the LMNA promoter contains a retinoic acid responsive element, we investigated if all-trans retinoic acid administration could lower progerin levels in cultured fibroblasts. We also evaluated the effect of associating rapamycin, which induces autophagic degradation of progerin and prelamin A. We demonstrate that all-trans retinoic acid acts synergistically with low-dosage rapamycin reducing progerin and prelamin A, via transcriptional downregulation associated with protein degradation, and increasing the lamin A to progerin ratio. These effects rescue cell dynamics and cellular proliferation through recovery of DNA damage response factor PARP1 and chromatin-associated nuclear envelope proteins LAP2α and BAF. The combined all-trans retinoic acid-rapamycin treatment is dramatically efficient, highly reproducible, represents a promising new approach in Hutchinson-Gilford Progeria therapy and deserves investigation in ageing-associated disorders.

Topics: Antineoplastic Agents; Blotting, Western; Cell Cycle; Cell Proliferation; Cells, Cultured; DNA-Binding Proteins; Drug Synergism; Fibroblasts; Gene Expression; Histones; Humans; Lamin Type A; Lysine; Membrane Proteins; Methylation; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Nuclear Proteins; Phenotype; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Progeria; Reverse Transcriptase Polymerase Chain Reaction; Sirolimus; Tretinoin