Optimization of a method to reduce expression of progerin, the cause of HGPS (Pro

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DESCRIPTION (provided by applicant): This proposal seeks to develop a specific and efficient means to reduce or eliminate the production of the progerin protein, the cause of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). A de novo point mutation in codon 608 of the lamin A/C gene is present in nearly all cases of HGPS. This dominant gain-of-function mutation alters the processing of lamin A pre-mRNA and leads to the production of progerin. We have demonstrated the feasibility of this new approach that alters the processing of lamin A. The goal of this proposal is to produce and test a large library of candidate molecules for their ability to alter lamin A processing in the context of a marker gene. A small number of candidate molecules that most efficiently alter the production of the marker will be selected and tested individually in HGPS patient-derived cells. From these, a few lead candidate molecules that most specifically and efficiently reduce the production of progerin will be selected for further evaluation in Phase II if the results warrant continuation. PUBLIC HEALTH RELEVANCE: Children with Hutchinson-Gilford Progeria Syndrome suffer from many of the symptoms associated with normal physiologic aging. Death, usually from stroke or heart attack, occurs at a mean age of 13. At present, there is no treatment for this gain-of-function dominant mutation, although there are a number of approaches currently under investigation.