Cardiovascular Progerin Suppression and Lamin A Restoration Rescue Hutchinson-Gilford Progeria Syndrome

• Published in: Circulation (New York, N.Y.) Vol. 144; no. 22; pp. 1777 - 1794
• Main Authors: Sánchez-López, Amanda, Espinós-Estévez, Carla, González-Gómez, Cristina, Gonzalo, Pilar, Andrés-Manzano, María J, Fanjul, Víctor, Riquelme-Borja, Raquel, Hamczyk, Magda R, Macías, Álvaro, Del Campo, Lara, Camafeita, Emilio, Vázquez, Jesús, Barkaway, Anna, Rolas, Loïc, Nourshargh, Sussan, Dorado, Beatriz, Benedicto, Ignacio, Andrés, Vicente
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 30.11.2021
• Subjects: Animals; Disease Models, Animal; Humans; Lamin Type A - genetics; Lamin Type A - metabolism; Mice; Mice, Transgenic; Muscle, Smooth, Vascular - metabolism; Myocytes, Cardiac - metabolism; Myocytes, Smooth Muscle - metabolism; Original s; Progeria - genetics; Progeria - metabolism; smooth muscle; Hutchinson-Gilford progeria syndrome; cell; cardiac myocyte
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.121.055313

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder characterized by premature aging and death mainly because of myocardial infarction, stroke, or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Patients look healthy at birth, and symptoms typically emerge in the first or second year of life. Assessing the reversibility of progerin-induced damage and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies. We used CRISPR-Cas9 technology to generate ( ) mice engineered to ubiquitously express progerin while lacking lamin A and allowing progerin suppression and lamin A restoration in a time- and cell type-specific manner on Cre recombinase activation. We characterized the phenotype of mice and crossed them with Cre transgenic lines to assess the effects of suppressing progerin and restoring lamin A ubiquitously at different disease stages as well as specifically in vascular smooth muscle cells and cardiomyocytes. Like patients with HGPS, mice appear healthy at birth and progressively develop HGPS symptoms, including failure to thrive, lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electrocardiographic anomalies, and precocious death (median lifespan of 15 months versus 26 months in wild-type controls, <0.0001). Ubiquitous progerin suppression and lamin A restoration significantly extended lifespan when induced in 6-month-old mildly symptomatic mice and even in severely ill animals aged 13 months, although the benefit was much more pronounced on early intervention (84.5% lifespan extension in mildly symptomatic mice, <0.0001, and 6.7% in severely ill mice, <0.01). It is remarkable that major vascular alterations were prevented and lifespan normalized in mice when progerin suppression and lamin A restoration were restricted to vascular smooth muscle cells and cardiomyocytes. mice constitute a new experimental model for advancing knowledge of HGPS. Our findings suggest that it is never too late to treat HGPS, although benefit is much more pronounced when progerin is targeted in mice with mild symptoms. Despite the broad expression pattern of progerin and its deleterious effects in many organs, restricting its suppression to vascular smooth muscle cells and cardiomyocytes is sufficient to prevent vascular disease and normalize lifespan.