Blocking ICMT Identified as Possible Treatment Approach for Progeria

Researchers have identified a potential new treatment approach for Hutchinson-Gilford progeria syndrome (HGPS). The findings, published in eLife, show that blocking a protein called ICMT can improve the condition of affected cells without reducing cell division and growth. 

These results suggest that ICMT could be a useful drug target to treat HGPS, especially as cell division and growth are important for development in children. Current treatments for HGPS prevent the farnesylation of progerin, but although these drugs improve some symptoms in patients, they can stop cells from multiplying. "Previous research has raised the possibility that inhibiting ICMT activity could be an effective therapeutic strategy," explains first author Xue Chen. "We wanted to determine if these therapeutic benefits would be seen in living mice with HGPS and whether we could use existing drugs to safely reproduce the effects of genetic inactivation on a cellular level."

To do this, the researchers used mice with HGPS that produced progerin and inactivated the ICMT gene, observing how it affected their health. They found that the mice which lacked ICMT survived significantly longer, and had higher body weights, compared to unmodified mice with progeria. They also had larger skeletal muscle fibres, and the muscle cells around their aorta, resembled those of healthy mice.

The team next treated HGPS cells and the HGPS-mimicking cells from mice with a synthetic chemical called C75 that strongly inhibited the ICMT protein. This treatment delayed the deterioration of the cells and stimulated cell division and growth. Importantly, when applied to healthy human cells and mouse cells that lacked the target ICMT protein, C75 had no significant unintended effects, meaning that it has good specificity for HGPS. "Our study has taken important steps in validating ICMT as a potential drug target that could provide advantages over existing treatments for children with this fatal condition," concludes senior author Martin Bergo.  "Further studies are now needed to find compounds that can target ICMT in living organisms, not just in cells."