Wed. Dec 1st, 2021

It is never too late to treat progeria

Aorta from a healthy mouse (left) and an HGPSrev mouse with progeria. As in HGPS patients, the cells in the HGPSrev aorta express progerin (white nuclei), and the aorta shows signs of loss of vascular smooth muscle cells (blue nuclei) and prominent vascular fibrosis (green signal). Credit: CNIC

Researchers at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and the Spanish Cardiovascular Research Network (CIBERCV), led by Dr. Vicente Andrés, has generated the experimental mouse model HGPSrev. This is the first animal model to develop Hutchinson-Gilford Progeria Syndrome (HGPS) and allow its suppression through the controlled regulation of the expression of progerin, the aberrant protein that causes the disease. Using the new model, researchers have shown that it is never too late to treat HGPS.

The study, published today in Circulation, also states that the cardiovascular changes and premature death associated with HGPS can be prevented with treatments that specifically target cells in the cardiovascular system.

HGPS is an ultra-rare genetic disease that affects fewer than 400 children worldwide and for which there is no known cure. The disease is caused by a mutation in the LMNA gene and is characterized by accelerated aging and death in the second decade of life, primarily due to cardiovascular complications derived from atherosclerosis.

In the absence of mutations, the LMNA encodes type A lamin proteins (lamin A and C). The mutation found in HGPS patients results in the synthesis of progerin, a mutant protein that induces several molecular and cellular changes in the tissues where it accumulates, causing their lives to pass at a rapidly accelerated rate, where minutes are hours and hours are lost days.

Now, thanks to the HGPSrev mouse generated by the CNIC Molecular and Genetic Cardiovascular Pathophysiology group, the research team has managed to suppress progerin expression and re-establish lamin A expression in mice of different ages, both in all body tissues and in specific cell types.

The characterization of the animal model was performed with the participation of researchers at Queen Mary University of London.

Joint first authors Dr. Amanda Sánchez López and Carla Espinós Estévez explained that while some palliative therapies are effective in animal models and are the subject of clinical trials, their therapeutic benefit is very limited. “A true cure would require elimination of the culprit mutation,” commented Dr. Sánchez López.

However, this is not yet possible and progeria is only diagnosed when the first symptoms have already appeared. “We therefore sought to reverse the symptoms when they are already present and to determine how long the treatment could be delayed and still have a beneficial effect,” explained Dr. Espinós Estévez.

The extent to which the damage caused by progerin can be reversed is not known at present, and patients often do not begin treatment until symptoms are fairly advanced. The investigators therefore addressed a key question: Can the progression of HGPS be stopped or slowed down if treatment is started when the disease is advanced, or does the therapeutic benefit depend on starting treatment early when the symptoms are mild?

Another important question is how the treatment should be targeted. Progerin is expressed in many tissues, but it was not known whether the treatment should target all affected cells or whether it would be effective if targeted to a specific cell type.

It is never too late to treat progeria

Scheme of the genetic construct used to generate HGPSrev mice, indicating reversion of the allele by the action of Cre recombinase. The representative images show the expression of progerin (white nuclear signal) in the heart of an HGPSrev mouse. Credit: CNIC

To answer these questions, Dr. Andrés’ team CRISPR-Cas9 technology to generate HGPSrev mice.

The results published today in Circulation shows that HGPSrev mice develop major features of human disease, including growth retardation, lipodystrophy, cardiovascular changes, and premature death.

The researchers also showed that eliminating progerin and restoring lamin A expression increased life expectancy by 84.5% in HGPSrev mice with very mild symptoms, and further prolonged life by 6.7% even in mice with very advanced symptoms.

These results not only establish that starting treatment when the symptoms are mild has a huge positive effect, but also that the treatment can be beneficial no matter how late it is started.

“We were able to prevent vascular changes and normalize survival in progeric mice by eliminating progerin expression and restoring lamin A expression specifically in vascular smooth cells and cardiomyocytes, although other cell types remained diseased,” explained Dr. Andrés.

The researchers conclude that these results “could contribute to the design of future clinical treatments, given that they suggest that strategies aimed solely at the cardiovascular system may have a very significant beneficial effect on patients’ quality of life and life expectancy.”

Researchers discover the cause of accelerated atherosclerosis and premature death in progeria

More information:
Amanda Sánchez-López et al., Cardiovascular Progerin Suppression and Lamin A Restoration Rescues Hutchinson-Gilford Progeria Syndrome Circulation (2021). DOI: 10.1161 / CIRCULATIONAHA.121.055313

Provided by the Carlos III National Center for Cardiovascular Research (FSP)

Citation: It’s never too late to treat progeria, say researchers (2021, October 26) retrieved October 27, 2021 from

This document is subject to copyright. Apart from any reasonable trade for the purpose of private investigation or research, no part may be reproduced without written permission. The content is provided for informational purposes only.

Leave a Reply

Your email address will not be published. Required fields are marked *