News: Farnesyl transferase inhibitors may help children with Hutchinson-Gilford progeria
Kids with of Hutchinson-Gilford progeria (HGPS) suffer a fast and devastating kind of accelerating aging syndrome. They experience many symptoms common to normal senility, as atherosclerosis, osteoporosis and hair loss. The life expectancy of HGPS children is extremely short. Most of them die in their early teens. The gene responsible of typical HGPS has been identified in 2003. HGPS is due to mutations in the lamin A gene.
Lamins are proteins that belong to the nuclear lamina, a network of proteins underlying the inner nuclear membrane. In normal cells, prelamin A attaches to the inner nucleus membrane. The attachment to the membrane is done by adding a farnesyl group to the prelamin A. This modification is done by an enzyme called farnesyl transferase (FT). Once farnesylated prelamin A is bound to the nucleus membrane, another enzyme called ZMPSTE24 trims it to render functional lamin.
HGPS patients have prelamin versions that are not cut by ZMPSTE24, so the non functional farnesylated prelamin accumulates, leading to problems in nucleus morphology and function.
A group from an UCLA team has raised hopes of having a treatment to alleviate HGPS kids. They used mice deficient in ZMPSTE24 to determine if FT inhibitors could ameliorate the progression of HGPS. Treated with ABT-100 (a FT inhibitor), mice mutant of ZMPSTE24 had less osteoporosis, better growth and, less drop in grip strength than mutant mice not treated with ABT-100.
FT inhibitors were developed in the past as anticancer drugs, though they revealed disappointing in the clinic. Being FT inhibitors not too toxic, they could be used to treat HGPS. The results obtained with ABT-100 are expected to boost clinical trials with HGPS kids.