Analysis of genome function recovery upon pharmacological treatment in Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder that causes accelerated aging in children. Currently, no cure is available for this disorder and ongoing clinical trials do not revert the disease. Mutations causing HGPS syndrome fall on lamin A/C gene and generate a truncated form, the progerin, that, acting as a dominant negative, affects lamin A/C nuclear organization. The nuclear lamina is important for controlling the DNA three-dimensional structure, a key player in the regulation of genome functionality: i.e., how different portions of the genome are turned on or off in different cell types and tissues. The presence of progerin thus interfere with DNA structure determining some genome dysfunctions. In 2020 the first treatment of progeria with lonafarnib drug was approved in USA. Other drugs are in preclinical tests as progerinin. However, to date no studies were done on the role of lonafarnib or progerinin on the DNA conformation. Moreover, we have not been able to get a clear picture regarding the chromatin alterations because of the lack of adequate technologies to perform analyses in depth. In this project, we will use advanced experimental techniques, including methods that we developed in our laboratory, in the mouse model of HGPS, to identify chromatin structure alterations resistant to pharmacological treatments. This study will not only improve our basic knowledge of the disease but can lead to the identification of new targets for innovative therapies.