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New potential drug target for treating progeria

Scientists have identified a potential new treatment approach for a rare genetic disorder known as Hutchinson-Gilford progeria syndrome (HGPS).

Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome is a rare progressive genetic disorder that causes rapid and premature ageing in children. It is caused by accumulation of progerin – a mutated form of prelamin A. Progerin is farnesylated and methylated within the nuclear envelope. Farnesyltransferase inhibitors (FTIs) prevent progerin farnesylation and improve some clinical phenotypes of HGPS patients, yet the effect is modest. Also, these inhibitors are anti-proliferative and children with progeria would benefit more from a therapy that supports cell proliferation.

Researchers have found that inhibiting the methylation of progerin by inactivating the isoprenylcysteine carboxylmethyltransferase (ICMT) gene overcomes senescence and increases proliferation of HGPS cells. Additionally, in Zmpste24-deficient mice (model of progeria), researchers have found that knockout of Icmt substantially improved clinical phenotypes. These results raise the possibility that inhibiting ICMT activity could be a useful therapeutic strategy.

Inhibiting ICMT

In this study, published in eLife, researchers aimed to determine whether Icmt inactivation improved phenotypes in an authentic HGPS mouse model. They observed that knockout of Icmt improved survival of HGPS mice and restored vascular smooth muscle cell numbers in the aorta. This is particularly important as cardiovascular problems are the main cause of mortality in these children.

Then, the team synthesised a potent ICTM inhibitor called C75. They found that this inhibitor delayed senescence and stimulated proliferation of late-passage HGPS cells and Zmpste24-deficient mouse fibroblasts. Most importantly, they also discovered that C75 did not impact proliferation of wild-type human cells or Zmpste24-deficient mouse cells lacking Icmt. This indicates that the drug is specific.

These results provide hope that ICMT inhibitors may be useful drug candidates for treating children with HGPS.

Mohamed Ibrahim from the Sahlgrenska Center for Cancer Research, University of Gothenburg, stated:

“We hope these findings will further incentivise the development of efficacious compounds targeting ICMT.

This approach would also likely lack the detrimental properties of current protocols treating already frail children with drugs originally developed to treat cancer.”

Image credit: By Iryna Khabliuk –

More on these topics

Drug Discovery / Progeria / Rare Diseases