Non-coding RNAs in the disease pathogenesis of progeria (PROGERIA)

Research Context: Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder, caused by a de novo point mutation in the LMNA gene, leading to the production of a truncated lamin A protein, named progerin. Children show typical symptoms of accelerated aging within the first years of life and die before they are 20 years old due to age-linked cardiovascular problems and accelerated atherosclerosis. The underlying patho-mechanisms remain unclear, and several launched preclinical and clinical trials have shown only limited success. Hypothesis: Based on exciting recent work of the consortium members we hypothesize that newly emerging molecules in human cells that regulate several important cellular processes and pathways, so called non-coding RNAs (ncRNAs) are not functioning properly in HGPS cells, thereby causing many of the pathological hallmark features in HGPS cells, tissues and patients. Cellular defects potentially caused by ncRNAs in HGPS include the accumulation of DNA damage and an impaired regulation of gene expression. In addition, ncRNAs may also induce fibrosis in cardiovascular tissue leading to blood vessel stiffening and heart problems. Approach: State-of-the-art genome-wide sequencing technologies at the single cell level will be employed to identify novel HGPS-linked ncRNAs in cardiovascular tissue of HGPS mouse models, as well as in human cells derived from HGPS patients and in samples obtained from patients suffering from HGPS-related laminopathic diseases. Identified ncRNAs will be functionally tested for their involvement in HGPS- linked DNA damage, gene expression defects, and pro fibrotic signalling using cellular HGPS in vitro disease models. Finally, we will use novel drugs neutralizing the most potent ncRNAs in HGPS mouse models to confirm their causal involvement in disease pathology and test their feasibility as novel therapeutic reagents for treatment of HGPS patients Innnovation: ncRNAs are a hitherto underexplored aspect in the context of HGPS. We expect that our consortium will identify novel ncRNA-linked HGPS disease pathways, which can pave the way to new, more efficient therapeutic approaches based on ncRNA-neutralizing drugs. Research partners: The transnational and interdisciplinary project involves scientists from Sweden, Italy, Austria and Germany, including experts in HGPS animal models and in molecular biological analyses of cellular phenotypes, as well as a clinical researcher involved in diagnosis and treatment of HGPS-related patients and the world-wide largest progeria patient advocacy organization (PRF https://www.progeriaresearch.org)

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic premature aging disease. Children are normal at birth but during their first years of life they start developing typical symptoms of accelerated aging, including severe growth retardation, loss of subcutaneous fat and hair, age-appearing skin and bone defects. Additionally, the life-threatening problem in these children is an accelerated onset of atherosclerosis and cardiovascular disease, leading to heart failure at an average age of 15. The disease is caused by a mutation in a protein in the cell nucleus disturbing many cellular functions. Even though the genetic cause for the disorder was defined 15 years ago, the underlying disease mechanisms responsible for cardiovascular disease are still unknown, and several launched clinical trials for patient treatment have shown only limited success. The development of more efficient therapeutic approaches needs a better insight into cellular pathways and processes impaired in patient cells and tissues, particularly the cardiovascular tissue. In this network project, involving partners from Sweden, Germany, Italy and the United States, we took a novel approach, investigating a hitherto underexplored potential role of a specific class of biomolecules, called non-coding (nc) RNAs in progeria disease mechanisms. These molecules have increasingly been recognized as factors regulating many cellular pathways during normal tissue development and tissue regeneration. Our project tested whether a dysregulation of these biomolecules may also contribute to cardiovascular disease in progeria. We focused on a specific cell type lining the inner surface of blood vessel, as these cells are known to contribute to atherosclerosis development during normal aging. We found that in progeria, these cells have problems to respond to changes in shear stress generated by the blood flow under physiological conditions. This, in turn initiates an abnormal production of a subgroup of ncRNA molecules and their secretion into the blood stream, where these molecules can then spread throughout the body. The blood vessel cells abnormally producing these ncRNA molecules undergo a so-called cellular aging process impairing their normal function and causing stiffening of the blood vessels, a hallmark of cardiovascular disease. In addition, these cells can signal to other healthy cells through the secreted ncRNA molecules, causing defects in various organs, such as bone. In search for therapeutic strategies to treat these symptoms we tested novel drugs that target and destroy the deregulated ncRNAs, and found partial rescue of some of the deregulated pathways. Overall, our project can pave the way to new, more efficient therapeutic approaches for premature aging disease based on ncRNA-neutralizing reagents, but also for treating aging-linked diseases in general.