Development of a New Therapeutic Approach for Prelamin A Diseases

描述(申请人提供)：我们的目标是了解Prelamin A和Lamin C(LMNA基因的另一种剪接产物)在健康和疾病中的功能，并开发新的策略来治疗Prelamin A疾病，包括黄体综合征。在这项应用中，我们将探索一种新的治疗前层蛋白A疾病的策略，这是由中枢神经系统中层蛋白A生物学的新发现所提出的。典型的儿童黄体综合征，Hutchinson-Gilford Progeria综合征(HGPS)，是由Prelamin A的突变形式引起的。受影响的儿童在出生时是健康的，但很快就会发展成几种类似早衰的疾病表型。在过去的9年里，我们一直致力于研究核板的生物学，着眼于寻找基于机制的治疗核板疾病(椎板病)的方法。这一方法使我们在2004年提出，蛋白质法尼化可能在Pre lamin A相关孕激素综合征的发病机制中起重要作用。从那时起，我们在早衰症的小鼠模型中测试了蛋白法尼基转移酶(FTI)的抑制剂，这促使了一项针对HGPS儿童的FTI临床试验。这项试验已经完成，FTI似乎改善了几种疾病表型。然而，非常明显的是，FTI治疗远远不能治愈，无论是在小鼠模型上还是在 人类。需要新的治疗策略。我们最近发现了Lamin A生物学的一个新特征，这为前Lamin A疾病的新治疗策略提供了一条途径。我们发现神经元表达层蛋白C，但很少表达前蛋白A。这一观察结果可能解释了为什么患有HGPS的儿童免受神经退行性疾病的影响。更重要的是，我们的观察促使我们认真思考早衰症的新治疗策略。前层蛋白A的合成在大脑中可以忽略不计，在HGPS中大脑不会受到疾病的影响。如果我们能找到降低外周组织中前层素A水平的策略(反映大脑的情况)，就有可能预防--甚至逆转--这种疾病 HGPS和其他Prelamin A疾病的表型。在接下来的5年里，我们将研究大脑调节前层蛋白A合成的机制。此外，我们还将研究调控层粘连蛋白C和前粘连蛋白A合成的DNA序列和蛋白质。我们还将致力于表征反义寡核苷酸，这些寡核苷酸改变剪接并以牺牲前层蛋白A为代价，使天平向层蛋白C的产生倾斜。最后，我们将确定减少外周组织中前层蛋白A的合成是否改善了一种新的HGPS小鼠模型的疾病表型。

DESCRIPTION (provided by applicant): Our objectives are to understand the function of prelamin A and lamin C (alternatively spliced products of the LMNA gene) in health and disease, and to develop new strategies to treat prelamin A diseases, which include progeroid syndromes. In this application, we will explore a new therapeutic strategy for prelamin A diseases that was suggested by a new discovery in lamin A biology in the central nervous system. The classic progeroid syndrome of children, Hutchinson-Gilford progeria syndrome (HGPS), is caused by a mutant form of prelamin A. Affected children are healthy at birth but soon develop several disease phenotypes that resemble premature aging. For the past 9 years, we have worked to investigate the biology of nuclear lamins with an eye towards finding mechanism-based therapies for diseases of the nuclear lamina (laminopathies). This approach led us to propose, in 2004, that protein farnesylation might be important for the pathogenesis of prelamin A-related progeroid syndromes. Since then, we have tested inhibitors of protein farnesyltransferase (FTIs) in mouse models of progeria, which prompted an FTI clinical trial in children with HGPS. That trial has been completed, and it appeared that the FTI improved several disease phenotypes. However, it is very clear that FTI treatment falls far short of a cure, both in mouse models and in humans. Fresh therapeutic strategies are needed. We recently uncovered a novel feature of lamin A biology that suggested a pathway to a new treatment strategy for prelamin A diseases. We discovered that neurons express lamin C but very little prelamin A. This observation likely explains why children with HGPS are spared from neurodegenerative disease. More importantly, our observation led us to think seriously about new therapeutic strategies for progeria. Prelamin A synthesis is negligible in the brain, and the brain is spared from disease in HGPS. If we can identify strategies for reducing prelamin A levels in peripheral tissues (mirroring the situation in the brain), it might be possible to prevent-or even reverse-the disease phenotypes of HGPS and other prelamin A diseases. For the next 5 years, we will investigate mechanisms by which the brain regulates prelamin A synthesis. In addition, we will investigate the DNA sequences and proteins that regulate lamin C and prelamin A synthesis. We will also work to characterize antisense oligonucleotides that alter splicing and tip the balance towards lamin C production at the expense of prelamin A. Finally, we will determine if reducing prelamin A synthesis in peripheral tissues ameliorates disease phenotypes in a new mouse model of HGPS.