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

描述(由申请人提供)：这项建议寻求开发一种具体而有效的方法来减少或消除孕激素蛋白的产生，孕激素蛋白是导致早衰症Hutchinson-Gilford Progeria综合征(HGPS)的原因。几乎所有的HGPS都存在Lamin A/C基因608密码子的新基因突变。这种显性的功能获得突变改变了层蛋白A前-mRNA的加工，并导致孕激素的产生。我们已经证明了这种改变层蛋白A加工的新方法的可行性。本提案的目标是生产和测试一个大的候选分子文库，以了解它们在标记基因的背景下改变层蛋白A加工的能力。将选择少量最有效地改变标记产生的候选分子，并在HGPS患者来源的细胞中单独进行测试。从这些中，如果结果证明可以继续，那么将选择几个最具体和最有效地减少孕激素产生的主要候选分子在第二阶段进行进一步评估。 公共卫生相关性：患有Hutchinson-Gilford Progeria综合征的儿童患有许多与正常生理衰老相关的症状。死亡通常死于中风或心脏病发作，平均年龄为13岁。目前，这种功能获得型显性突变还没有治疗方法，尽管目前有许多方法正在研究中。

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.