New mouse model shows it’s never too late to treat Hutchinson-Gilford Progeria syndrome


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

The study, published today in Circulation, also establishes that the cardiovascular damage and early death associated with HGPS can be prevented with treatments specifically targeting cells of 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 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 a mutation, LMNA code for laminated proteins of type A (Lamins A and C). The mutation found in patients with HGPS results in the synthesis of progerin, a mutant protein that causes multiple molecular and cellular alterations in the tissues where it accumulates, causing their lives to pass at a very accelerated rate, where minutes are hours and hours are wasted days. .

Now, thanks to HGPSrev mouse generated by CNIC’s molecular and genetic cardiovascular pathophysiology group, the research team succeeded in suppressing progerin expression and restoring lamin A expression in mice of different ages, both in all tissues of the body and in specific cell types.

The characterization of the animal model was carried out with the participation of researchers from Queen Mary University in London.

The first joint authors, Drs Amanda Sánchez López and Carla Espinós Estévez, explained that while some palliative therapies are effective in animal models and are in clinical trials, their therapeutic benefit is very limited. “A real cure would require removing the culprit mutation,” commented Dr Sánchez López. However, this is not yet possible and progeria is not diagnosed until the first symptoms have already appeared.

We therefore sought to reverse the symptoms once they were already present and to determine how long treatment could be delayed while still having a beneficial impact. “

Dr Carla Espinós Estévez, first author

The extent to which the damage caused by progerin can be reversed is currently not known, and patients often do not begin treatment until symptoms are quite advanced. The researchers therefore addressed a key question: Can the progression of HGPS be stopped or slowed if treatment begins when the disease is advanced, or does the therapeutic benefit depend on starting treatment early, when 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 treatment should be directed against all affected cells or whether it would be effective if targeted to a specific cell type.

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

The results published today in Circulation CA watch HGPSrev mice develop the main features of human disease, including growth retardation, lipodystrophy, cardiovascular damage, and premature death.

The researchers also showed that removing progerin and restoring lamin A expression increased life expectancy by 84.5% in children. HGPSrev mice showing very mild symptoms and, moreover, a 6.7% prolonged lifespan even in mice showing very advanced symptoms.

These results establish not only that starting treatment when symptoms are mild has a huge positive impact, but also that treatment can be of benefit regardless of what time it is started.

“We were successful in preventing vascular damage and normalizing survival in progeric mice by eliminating progerin expression and restoring lamin A expression specifically in vascular smooth cells and cardiomyocytes, although other types of cells remained sick, ”explained Dr. Andrés.

The researchers conclude that these findings “could contribute to the design of future clinical treatments, as they suggest that strategies exclusively targeting the cardiovascular system could have a very significant beneficial effect on the quality of life and life expectancy of patients. patients “.


Centro Nacional de Investigaciones Cardiovasculares Carlos III (FSP)

Journal reference:

Sanchez-Lopez, A., et al. (2021) Removal of cardiovascular progerin and restoration of lamin A saves Hutchinson-Gilford Progeria syndrome. Circulation.


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