Researchers have discovered a promising treatment method for Hutchinson-Gilford progeria syndrome (HGPS)—a debilitating genetic disorder that accounts for rapid and premature aging in children.
Progeria. Image Credit: Jack_the_sparow/Shutterstock.com
The mice results, published recently in the eLife journal, demonstrate that inhibiting a protein, known as ICMT, can enhance the condition of the impacted cells without decreasing the division and growth of cells. The ICMT protein plays a key role in changing the progerin structure. Progerin is a mutant protein that is responsible for causing HGPS.
Such results indicate that the ICMT protein could be a valuable drug target for treating HGPS, particularly as division and growth of cells are crucial for development in children.
HGPS is induced by the mutant protein progerin, which experiences two kinds of structural changes, known as methylation and farnesylation. Progerin builds up between the membrane surrounding the cell nucleus, resulting in damage that causes cells to delay their growth and die too soon.
Existing HGPS treatments inhibit the farnesylation of progerin, but while these medications enhance a few symptoms in patients, they can prevent cells from multiplying.
Earlier experiments have indicated that deactivating the gene for the ICMT protein, which usually results in the methylation of progerin, can also enhance major symptoms, and at the same time prevent the effects on growth and division of cells. But such advantages have only been shown in HGPS cells beyond the body and in mice with a simulation of the disease.
Previous research has raised the possibility that inhibiting ICMT activity could be an effective therapeutic strategy. 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.”
Xue Chen, Study First Author and PhD Student, Department of Biosciences and Nutrition, Karolinska Institutet
To achieve this, the team first utilized mice affected by HGPS that generated progerin, then disabled the ICMT gene, and finally observed how it impacted the animals’ health.
The researchers found that the mice lacking the ICMT protein survived considerably longer, and also had increased body weights when compared to unmodified mice with HGPS. This set of animals also had larger skeletal muscle fibers, and the muscle cells found around their aorta—the massive artery in the heart required for carrying oxygen-rich blood—looked like those of healthy mice. This outcome is specifically significant since cardiovascular issues are the major cause of death in children afflicted with HGPS.
Then using a synthetic chemical known as C75 that powerfully blocked the ICMT protein, the researchers treated the HGPS cells as well as the HGPS-mimicking cells obtained from mice. This treatment slowed the cell deterioration and activated cell division and development.
Most significantly, when the C75 chemical was applied to healthy mouse cells and human cells lacking the target ICMT protein, it had no major inadvertent effects, which means it has excellent specificity for HGPS.
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.”
Mohamed Ibrahim, Study Author, Sahlgrenska Center for Cancer Research, University of Gothenburg
The researchers then examined where the progerin protein builds up in cells treated with the C75 chemical. They observed that progerin builds up within the cell nucleus—the center of the cell. This indicates that inhibiting the methylation of progerin by ICMTs redirects these proteins and decreases their potential to cause damage.
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. Further studies are now needed to find compounds that can target ICMT in living organisms, not just in cells.”
Martin Bergo, Study Senior Author and Professor, Department of Biosciences and Nutrition, Karolinska Institutet
Source:
Journal reference:
Chen, X., et al. (2021) A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells. eLife. doi.org/10.7554/eLife.63284.