They identify the key cells to prevent atherosclerosis in progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease that affects 1 in 20 million people. It is estimated to affect fewer than 400 children worldwide. The disease is characterized by inducing accelerated aging, severe atherosclerosis and premature death at an average age of approximately 15 years.

Although HGPS patients usually do not have the typical cardiovascular risk factors (hypercholesterolemia, obesity, smoking, etc.), their main cause of death is complications of atherosclerosis, such as myocardial infarction, stroke or heart failure.

Given that there is currently no cure for progeria, it is urgent to develop new therapies that prevent atherosclerosis and other vascular alterations associated with the disease to increase the life expectancy of patients.

The genetic cause of HGPS is a mutation in the LMNA gene that causes the expression of progerin, a mutant version of the nuclear protein lamin A that induces numerous harmful effects at the cellular and organismal levels.

Recent studies carried out in animal models of this syndrome have shown that it is possible to correct this mutation through gene editing, and that the consequent elimination of progerin and recovery of lamin A expression improves the characteristic alterations of HGPS and prolongs life expectancy.

In order to optimize gene therapy for the potential treatment of patients with progeria, it is important to identify the cell types in which progerin deletion produces the most benefits.

To face this challenge, the laboratory of Dr. Vicente Andrés, from the Carlos III National Center for Cardiovascular Research (CNIC) and the Network Biomedical Research Center for Cardiovascular Diseases (CIBERCV), in Spain, began by generating a mouse genetically modified, the HGPSrev, in which key aspects of the disease can be studied in depth. The results of that study were published in the academic journal Circulation and pointed to vascular smooth muscle cells as a possible therapeutic target to combat premature atherosclerosis in progeria.

“This progeria model expresses progerin and lacks lamin A throughout the organism, and allows the elimination of progerin and the restoration of lamin A in specific cell types and in different phases of the disease,” explains Dr. Andrés.

Now in a new study, using HGPSrev mice, Ignacio Benedicto, from the Margarita Salas Biological Research Center, attached to the Higher Council for Scientific Research (CSIC) in Spain, and the group of Dr. Vicente Andrés, in collaboration with the University of Oviedo in Spain and Queen Mary University of London in the United Kingdom have studied whether HGPS-associated atherosclerosis can be prevented by suppressing progerin and restoring lamin A in endothelial cells or vascular smooth muscle cells, “two types.” cells of the arterial wall that play a key role in the development of conventional atherosclerosis,” explains Dr. Benedicto.

Members of the research team. (Photo: CNIC)

The researchers found that removing progerin from endothelial cells had no benefit. Atherosclerosis, arterial fibrosis, vascular inflammation, weight loss, and premature death were observed in these mice identically to mice with whole-body progerin expression.

On the contrary, those HGPSrev mice in which progerin was eliminated in vascular smooth muscle cells showed a level of atherosclerosis identical to that developed by normal mice without progerin expression, and they also did not have excess arterial fibrosis and vascular inflammation.

“These results suggest that correction of the mutation causing HGPS in vascular smooth muscle cells could be sufficient to produce a significant therapeutic benefit,” emphasizes Dr. Benedicto.

Dr. Andrés concludes that “a strategy of this type would probably require lower doses of gene editing reagents than those necessary for the elimination of progerin throughout the body, which could increase the possibility of developing more effective and safer future clinical applications. ”.

Dr. Andrés highlights the importance of researching rare or minority diseases, although they affect a small number of patients. According to Dr. Andrés “considered globally, they represent a health-social problem of great magnitude, since it is estimated that there are nearly 7,000 rare diseases that affect 7% of the world population (in Spain, more than 3 million patients). . Two of the big problems that these patients face are the lack of adequate diagnosis and treatment, largely due to insufficient research on these pathologies. In the case of progeria, there is currently no cure and existing palliative therapies are of limited benefit. Therefore, it is necessary to continue researching to advance our knowledge of the mechanisms by which progerin accelerates aging and to develop new therapies and, eventually, a cure for this disease.”

The study is titled “Exacerbated atherosclerosis in progeria is prevented by progerin elimination in vascular smooth muscle cells but not endothelial cells.” And it has been published in the academic journal Proceedings of the National Academy of Sciences (PNAS). (Source: CNIC)