Development of a New Therapeutic Approach for Prelamin A Diseases

Prelamin A 疾病新治疗方法的开发

• 批准号: 9027789
• 负责人: Loren Gi Fong
• 金额: $ 31.57万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027789
• 关键词: Affect; Aging; Antisense Oligonucleotides; Binding; Binding Sites; Biology; Birth; Brain; Cell Nucleus; Cells; Central Nervous System Diseases; Child; Clinical Trials; DNA Sequence; Development; Disease; Enhancers; Equilibrium; Exons; Eye; Farnesyl Transferase Inhibitor; Fibroblasts; Gene Targeting; Genes; Genetic; Genetic study; Goals; Health; Human; In Vitro; Knock-in; Knock-in Mouse; Lamin Type A; Lead; Lipids; Lonafarnib; Mammalian Cell; MicroRNAs; Modeling; Molecular; Mus; Mutation; Neuraxis; Neurodegenerative Disorders; Neurological observations; Neurons; Nuclear; Nuclear Lamin; Nucleotides; Paper; Pathogenesis; Pathway interactions; Peripheral; Play; Premature aging syndrome; Production; Progeria; Property; Protein Farnesylation; Protein Isoforms; Proteins; Publications; RNA Splicing; Reagent; Regulation; Research; Role; Senile dementia; Structure; Syndrome; Techniques; Testing; Therapeutic; Thinking; Tissues; United States National Institutes of Health; Untranslated Regions; Work; authority; base; disease phenotype; falls; farnesylation; follow-up; improved; in vivo; lamin C; mouse model; mutant; novel; novel therapeutic intervention; panacea; prelamin A; prevent; programs; public health relevance; treatment strategy; virtual

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.

描述（由申请人提供）：我们的目标是了解前核纤层蛋白A和核纤层蛋白C（LMNA基因的选择性剪接产物）在健康和疾病中的功能，并开发治疗前核纤层蛋白A疾病（包括早衰综合征）的新策略。在本申请中，我们将探索一种新的治疗策略，前核纤层蛋白A疾病，这是由核纤层蛋白A生物学在中枢神经系统中的新发现所提出的。 Hutchinson-Gilford早老综合征（HGPS）是一种典型的儿童类早老综合征，由核纤层蛋白A前体的突变引起。受影响的儿童在出生时是健康的，但很快就会发展出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纤层蛋白的生物学，着眼于寻找基于机制的核纤层疾病（核纤层蛋白病）的治疗方法。这种方法使我们在2004年提出，蛋白质法尼基化可能是重要的前层蛋白A相关的早衰综合征的发病机制。从那时起，我们在早衰症小鼠模型中测试了蛋白法尼基转移酶（FTIs）的抑制剂，这促使了HGPS儿童的FTI临床试验。该试验已经完成，FTI似乎改善了几种疾病的表型。然而，很明显，FTI治疗福尔斯远不能治愈，无论是在小鼠模型中还是在小鼠模型中。 人类需要新的治疗策略。 我们最近发现了核纤层蛋白A生物学的一个新特征，为核纤层蛋白A前体疾病的新治疗策略提供了一条途径。我们发现神经元表达核纤层蛋白C，但很少表达核纤层蛋白A。这一观察结果可能解释了为什么患有HGPS的儿童免于神经退行性疾病。更重要的是，我们的观察使我们认真思考早衰症的新治疗策略。前体蛋白A的合成在大脑中可以忽略不计，并且大脑在HGPS中免于疾病。如果我们能找到降低外周组织中前层蛋白A水平的策略（反映大脑中的情况），就有可能预防-甚至逆转-这种疾病 HGPS和其他前层蛋白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，我们将研究调节核纤层蛋白C和前核纤层蛋白A合成的DNA序列和蛋白质。我们也将致力于表征反义寡核苷酸，其改变剪接并以牺牲前核纤层蛋白A为代价使平衡向核纤层蛋白C的生产倾斜。最后，我们将确定减少外周组织中的前层蛋白A合成是否能改善新的HGPS小鼠模型中的疾病表型。