Isoprenylcysteine carboxylmethyltransferase-based therapy 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.

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice

“…These studies were carried out as previously described with minor modifications. 41,42 The assessment of the membrane permeability of synthesized compounds and propranolol and metoprolol as reference compounds was performed in a commercially available 96-well Corning Gentest precoated PAMPA plate system (Cultek S.L.U., Spain). Prior to use, the precoated PAMPA plate system was warmed to rt for 30 min and 300 μL of 200 μM solution of tested compound in 2% DMSO in PBS (pH 7. precoated PAMPA plate until it sits on the receiver plate.…”

Status of treatment strategies for Hutchinson–Gilford progeria syndrome with a focus on prelamin: A posttranslational modification

“…Importantly, UCM‐13207 was also tested in progerin‐expressing mice in vivo where it was found to increase body weight and grip strength and reduce senescence markers in organs. Moreover, the drug reduces progerin levels in the aortic wall and increases the number of vascular smooth muscle cells and increases survival by 20% 36 …”

Toward a New Therapy for Rapidly Aging Children

“…In this issue of ACS Central Science , Marcos-Ramiro and co-workers take a big step forward by synthesizing and validating a potent ICMT inhibitor that can be used in vivo, which improved key phenotypes of mice with progeria and extended survival. 4 Although several hurdles remain, these results set the stage for future clinical trials in children with HGPS.…”