Inhibiting ICMT as a Progeria Therapy

Progress towards a therapy for the rare accelerated aging condition progeria continues. It remains unclear as to whether the mechanisms responsible for progeria exist in normal aging to a level that is in any way significant. Progeria is caused by malformed prelamin A, and tiny amounts of broken prelamin A can be found in old tissues - but it would really require a therapy for progeria that addressed the issues with prelamin A to easily find out whether this has any meaningful contribution to normal aging.

The classical form of progeria, called Hutchinson-Gilford Progeria Syndrome (HGPS), is caused by a spontaneous mutation, which means that it is not inherited from the parents. Children with HGPS usually die in their teenage years from myocardial infarction and stroke.

The progeria mutation occurs in the protein prelamin A and causes it to accumulate in an inappropriate form in the membrane surrounding the nucleus. The target enzyme, called ICMT, attaches a small chemical group to one end of prelamin A. Blocking ICMT, therefore, prevents the attachment of the chemical group to prelamin A and significantly reduced the ability of the mutant protein to induce progeria. "We are collaborating with a group in Singapore that has developed candidate ICMT inhibitor drugs and we will now test them on mice with progeria. Because the drugs have not yet been tested in humans, it will be a few years before we know whether these drugs will be appropriate for the treatment of progeria."

"The resemblance between progeria patients and normally-aged individuals is striking and it is tempting to speculate that progeria is a window into our normal aging process. The children develop osteoporosis, myocardial infarction, stroke, and muscle weakness. They display poor growth and lose their hair, but interestingly, they do not develop dementia or cancer." [The researchers are] also studying the impact of inhibiting ICMT on the normal aging process in mice.

Link: http://www.eurekalert.org/pub_releases/2013-05/uog-ptf051413.php

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