It is a rare genetic disease and as far as prior research goes, sufferers have little reason to hope for a long life. Those affected by Hutchinson-Gilford Progeria Syndrome (HGPS) show typical signs of old age already in childhood. Even as infants, patients suffer from atrophying muscles and bones or hair loss, and their cardiovascular system soon begins to cause additional problems. As early as in their teens, their blood vessels become clogged and atherosclerosis takes over. Many of the patients die of a heart attack before they reach the age of 20.
International research develops new focus
The genetic causes of progeria are well known. In the early 2000s, researchers discovered that a protein called lamin A was to blame. Mutations in the gene that codes for this protein can lead to a number of diseases, including progeria. The complex molecular mechanisms behind the progression of the disease, however, still confront researchers with many unknown factors. Existing treatments do little to slow down the course of the disease, and the average age at death is around 16. An ongoing international research project funded by the Austrian Science Fund FWF in Austria as part of the European Joint Programme on Rare Diseases (EJP RD) could now provide an opportunity for progress. It focuses on little-known influence factors in the course of the disease – so-called non-coding RNA.
Roland Foisner and his team at the Center for Medical Biochemistry at the Medical University of Vienna and at the Max Perutz Labs Vienna are joining forces with fellow researchers from Sweden, Italy and Germany in investigating the significance in progeria of these “transcripts of special genetic information”, as micro-RNA can be described. While studies have discovered only recently that they could play a role, it is still unclear what exactly that role is. In this project the researchers are cooperating with the US patient advocacy organization Progeria Research Foundation www.progeriaresearch.org, which supports relevant research worldwide.
Greater focus on non-coding RNA
Unlike its coding counterpart, non-coding microRNA is not designed to translate gene information into proteins. In the past it was assumed that it was something like cellular data trash. Nowadays, medical research is becoming more and more aware of its important regulatory functions. For example, it can “silence” genes and prevent them from becoming active. Dysfunctions in the regulation of microRNAs have already been linked to a number of diseases, including the formation of tumors. “We are investigating whether the presence of specific groups of non-coding RNAs are altered in progeria patients,” Foisner explains. “At the same time, we want to lay the foundation for new therapeutic approaches based on the regulation of micro-RNA.”
Foisner and his team have developed a mouse model that reproduces the disease in parts. “In a genetic disease, all cells produce the pathologically mutated gene. You don't know what the consequences are in different types of cells,” Foisner explains. “In our mouse model, we focus on one cell type – the endothelium, which makes up the inner lining of blood vessels.” Since cardiovascular problems are often the ultimate cause of death from the disease, a closer investigation of this cell type suggested itself. As a matter of fact, the mice with the progeria mutation in the endothelial cells showed the same clinical pictures that the researchers already knew from human patients.
Micro-RNA has an influence on cell ageing
Now the scientists are investigating the molecular mechanisms associated with non-coding RNA in these cells. “One consequence of a deregulated presence of micro-RNA can be so-called senescence, or cell ageing. The proportion of senescent cells in tissue contributes to the overall ageing process of the organism,” Foisner notes. “A large amount of ageing and dying cells also leads to a variety of inflammatory responses that can damage more cells and become a systemic problem.” Within the cell, non-coding RNA plays a role in the repair mechanisms of chromosomes in the cell nucleus, which become less efficient with age, as project partners from Italy have discovered. “We also know that in progeria many chromosome changes are present, which might be a secondary effect of micro-RNA deregulation,” says Foisner.
First studies with new active substance
The objective now is to develop an active substance that can keep deregulated micro-RNAs in check in the bloodstream. This could slow down cell ageing in the cardiovascular system and thus suppress at least a proportion of the symptoms of the disease. In a recently started study, substances that neutralize the micro-RNA are added to progeria mouse cells. Initial results are promising: “Many of the pathological changes in the cells were partially reversed,” Foisner explains. In order to verify the action mechanism and examine it in more detail, however, a series of further studies must be carried out on animal models before the method of treatment can be tested on humans in the course of a clinical phase. Foisner emphasizes that one cannot expect an approach of this kind to lead to a complete cure in a genetic disease. “In combination with other therapies, which are also currently being developed in preclinical studies, the suppression of certain RNA groups could, however, considerably prolong the life of progeria patients and improve their quality of life.”
Roland Foisner is Professor of Biochemistry at the Medical University of Vienna and a Senior Scientist at the Max Perutz Labs Vienna, where he also served as Deputy Director between 2007 and 2017. Foisner’s research specializes in the function of the cell nucleus and the role of lamin proteins. The project “Role of non-coding RNA in progeria disease mechanisms”, set to run from 2020 to 2023, received EUR 290,000 in funding from the Austrian Science Fund FWF.
Manakanatas C., Ghadge SK, Agic A., Sarigol F. et al.: Endothelial and systemic upregulation of miR-34a-5p fine-tunes senescence in progeria, in: Aging (Albany NY) 2022
Osmanagic-Myers S., Kiss A., Manakanatas C. et al.: Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse, in: The Journal of Clinical Investigation 2019