Potential drug target found for treating rare genetic disorder in children

A new study describes a potential drug target for Hutchinson-Gilford progeria syndrome that may aid in the development of more effective treatments. Scientists have identified a potential new treatment approach for Hutchinson-Gilford progeria syndrome (HGPS), a progressive genetic disorder that causes rapid and premature ageing in children.

The findings in mice, published in eLife, show that blocking a protein called ICMT can improve the condition of affected cells without reducing cell division and growth. ICMT is involved in modifying the structure of progerin, the mutant protein that causes HGPS.

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.

HGPS is caused by progerin, a mutant protein which undergoes two types of structural modifications called farnesylation and methylation. Progerin accumulates between the membranes that surround the cell nucleus, leading to damage that makes cells slow down their growth and die prematurely. 

Weight and muscles

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 experiments have suggested that inactivating the gene for the protein ICMT, which normally causes the methylation of progerin, can also improve key symptoms while avoiding the effects on cell growth and division. However, these benefits have only been demonstrated in HGPS cells outside the body and in mice with a mimic of the disease.

“Previous research has raised the possibility that inhibiting ICMT activity could be an effective therapeutic strategy,“ explains first author Xue Chen, a PhD student at the Department of Biosciences and Nutrition, Karolinska Institutet, Sweden. “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 – the large artery in the heart necessary for transporting oxygen-rich blood – resembled those of healthy mice. This result is particularly important as cardiovascular problems are the main cause of mortality in children with HGPS.

Potential strategy

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.

Photo of Mohamed Ibrahim and Martin Bergö
Corresponding authors Mohamed Ibrahim, University of Gothenburg and Martin Bergö, Karolinska Institutet.
Photo: Göteborgs universitet

“We hope these findings will further raise the interest in targeting ICMT as a potential strategy to help children with HGPS”, says Mohamed Ibrahim at Sahlgrenska Center for Cancer Research, University of Gothenburg.

“It is quite possible that our approach could be superior to current treatment strategies which are based on a compound that was developed for anti-cancer therapy and can inhibit proliferation and long-term survival of cells”, he says.

Next, the team studied where the progerin protein accumulates in cells treated with C75. They found that progerin accumulates inside the centre of the cell – the cell nucleus. This suggests that blocking the methylation of progerin by ICMT redirects the proteins and reduces their ability 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,” concludes senior author Martin Bergo, Professor at the Department of Biosciences and Nutrition, Karolinska Institutet. “Further studies are now needed to find compounds that can target ICMT in living organisms, not just in cells.”

Source: University of Gothenburg

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Next Post

Salt caverns to store hydrogen?

Fri Feb 5 , 2021
Deep underground, France hides deposits of crystallized salts over a large part of its territory. In total, more than 20,000km² of salt, hundreds of meters thick, were deposited by the ocean before being covered by sediments and other rocks. For several decades, industrialists have been exploiting the properties of salt […]

European Higher Education Organization is a public organization carrying out academic, educational and information activities on higher education in Europe.

The EHEO general plan stresses that:

  • Higher education systems require adequate funding and, as an investment in economic growth, public spending in higher education should be protected.
  • The challenges faced by higher education require more flexible governance and funding systems, which balance greater autonomy for education institutions with accountability to stakeholders.

Thus, EHEO plans:

  • improve academic and scientific interaction of universities;
  • protect the interests of universities;
  • interact more closely with public authorities of European countries;
  • popularize European higher education in the world;
  • develop academic mobility;
  • seek funding for European universities.