Isoprenylcysteine carboxylmethyltransferase basedtherapy for Hutchinson Gilford progeria syndrome

Abstract

Progerin is a mutant prelamin A variant that causes Hutchinson-Gilford progeria syndrome (HGPS, progeria), a rare genetic disease characterized by premature aging and death in childhood. Although several therapeutic approaches have been explored in experimental models, clinical trials have shown very limited benefits in HGPS patients. Here, we describe the development of UCM-13207, a new potent inhibitor of isoprenylcysteine carboxylmethyltransferase (ICMT) that reduces progerin nuclear accumulation and ameliorates the typical alterations in progeroid human and mouse cells. UCM-13207 also improves phenotypic anomalies and extends lifespan in progerin-expressing LmnaG609G/G609G mice. These results support the potential use of UCM-13207 as a new treatment for progeria.