The rarest of the rare – exploring non-coding RNA in the disease pathogenesis of Hutchinson-Gilford progeria syndrome

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Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder, caused by a de novo point mutation in the LMNA gene, leading to mis-splicing and production of a truncated lamin A protein, named progerin. Children show typical symptoms of accelerated aging and die in their teens due to accelerated atherosclerosis and cardiovascular disease. The underlying patho-mechanisms remain unclear, and clinical trials have shown only limited success. Based on exciting recent work of consortium members we hypothesize that non-coding RNAs (ncRNAs) are causally linked to pathological HGPS hallmark features at the cell, tissue and organismal level. These include the role of ncRNAs in HGPS-linked mis-splicing events, the contribution of damage-induced ncRNAs to DNA damage response (DDR) activation and induction of cellular senescence, and the role of intracellular and secreted micro RNAs (miRs) in pro-fibrotic signaling in cardiovascular tissue. State-of-the-art sequencing technologies at the single-cell level in cardiovascular tissue will be employed to identify ncRNAs in endothelial cell-specific- and in systemic HGPS mouse models, as well as in fibroblasts and induced pluripotent stem cells of patients and in various tissues of related laminopathic patients. Identified ncRNAs will be functionally tested for their involvement in DDR, mis-splicing, and pro fibrotic signalling in cellular HGPS disease models. Finally, we will use oligonucleotide-based drugs against the most promising ncRNAs in HGPS mouse models to study their causal involvement in disease pathology and test their potential as novel therapeutic reagents. ncRNAs are a hitherto underexplored aspect in the context of HGPS. We expect that our consortium will identify ncRNA-linked HGPS disease pathways, which can pave the way to new, more efficient therapeutic approaches based on ncRNA-neutralizing reagents (antisense oligos, antagomiRs). The transnational and interdisciplinary project involves principal investigators from Sweden, Italy, Austria and Germany, including experts in HGPS mouse models and in molecular biological analyses of cellular phenotypes, clinical researcher involved in diagnosis and treatment of laminopathic patients and the world-wide largest progeria patient advocacy organization (PRF https://www.progeriaresearch.org).