MOLECULAR MECHANISMS AND THERAPEUTIC APPROACHES TO THE HUCTHINSON- GILFORD PROGERIA SYNDROME

Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare and untreatable genetic disease characterized by premature aging of children. Common symptoms are hair loss, retarded growth, loss of facial fat, aged looking skin and severe hardening of the arteries. Affected children usually develop the disease during the first year of life and die in their teens for heart attacks and strokes. In 2003, researchers discovered that in 90% of cases HGPS is caused by a single spontaneous mutation in the LMNA gene, which produces lamin A, a fundamental protein that gives shape to the cell nucleus and controls many important cellular functions. The disease causing mutation leads to the production of progerin, an abnormal form of the lamin A protein. By conducting experiments in HGPS patient cells, it was possible to discover that progerin destabilizes the membrane of the nucleus and leads to severe malfunctions of the cell machinery that controls expression of genes, integrity of DNA and the life span of cells. Importantly, recent work has demonstrated that these defects are reversible and that they can be ameliorated by stopping the production of progerin in HGPS patient cells. These findings strongly suggest that a similar approach can be used as a therapeutic way to treat HGPS. With this aim in mind, we will study how malfunctions in the lamin A protein lead to HGPS, and we will develop new therapeutic strategies for HGPS. To this end, we will devise two complementary approaches: we will use gene therapy vectors capable of targeting the disease-causing mutation, and at the same time we will also search for chemical compounds that are able to stop progerin production. Altogether, these experiments will help us to understand the basic mechanisms that underlie HGPS and will explore novel treatment strategies for this disease.