Progeria is a very rare genetic disease characterised by dramatic premature ageing; Hutchinson-Gilford progeria syndrome (HGPS) is the most severe form of the disease. As newborns, children with progeria usually appear normal but, within one year, their growth rate declines. The children develop a distinctive appearance with alopecia, a small face and jaw and a pinched nose. They have small fragile bodies like those of elderly people and suffer symptoms typically associated with ageing, including joint stiffness and severe progressive cardiovascular disease. Affected children usually die in their early teens from complications of atherosclerosis such as heart attack or stroke.
Little research was carried out into the disease until the 1990s but it is now known that HGPS is caused by a mutation in the LMNA gene which encodes the nuclear membrane protein lamin A. Lamin A requires posttranslational farnesylation to be incorporated into the nuclear membrane; the C-terminal peptide, including the farnesyl group, is subsequently cleaved, and mature lamin A becomes a prominent component of the nuclear scaffold, affecting nuclear structure and function.
Farnesyl transferase inhibitors (FTIs), originally developed as anticancer drugs, have been shown to reduce disease significantly in animal models of HGPS. A phase II clinical trial using the FTI lonafarnib began in May 2007 and has an estimated completion date of October 2009.
A new study published in the Proceedings of the National Academy of Sciences describes the effect of another FTI, tipifarnib, in transgenic mice that develop cardiovascular disease similar to that seen in progeria patients. Tipifarnib was able to prevent, and even reverse, the cardiovascular damage in mice, giving hope that a similar effect will be seen in the patients treated with lonafarnib.