Modulating Lamin B1 levels as a therapeutic strategy for Autosomal Dominant Leukodystrophy

调节核纤层蛋白 B1 水平作为常染色体显性遗传性脑白质营养不良的治疗策略

• 批准号: 10643333
• 负责人: Quasar S Padiath
• 金额: $ 19.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643333
• 关键词: Adult; Age of Onset; Antisense Oligonucleotides; Applications Grants; Architecture; Autonomic Dysfunction; Behavioral; Biochemical; CNS degeneration; Cessation of life; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DNA cassette; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Disease Progression; Disease model; Down-Regulation; Effectiveness; Enterobacteria phage P1 Cre recombinase; Eukaryotic Cell; Excision; Exhibits; Gene Expression; Genes; Human; Injections; LMNB1 gene; Lamin B1; Life; LoxP-flanked allele; Modality; Molecular; Mus; Muscular Atrophy; Nuclear; Nuclear Inner Membrane; Nuclear Lamina; Oligodendroglia; Onset of illness; Pathologic; Pathology; Patients; Phenotype; Positioning Attribute; Pre-Clinical Model; Process; Proteins; RNA Interference; Side; Site; Spinal Cord; Symptoms; Tamoxifen; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; age related; autosome; disease phenotype; experimental study; in vivo; insight; leukodystrophy; motor disorder; motor symptom; mouse model; novel; overexpression; pre-clinical; prevent; promoter; protein expression; targeted treatment

Abstract Autosomal Dominant Leukodystrophy (ADLD) is a fatal, progressive adult-onset disease characterized by autonomic and motor dysfunction with widespread CNS demyelination. We have previously shown that ADLD is caused by duplications of the lamin b1 gene and that increased expression of lamin B1 underlies the disease process. In eukaryotic cells, lamin B1 is a major constituent of the nuclear lamina, a fibrous meshwork adjacent to the inner nuclear membrane. We have demonstrated that transgenic (TG) mice with oligodendrocyte specific over-expression of lamin B1 exhibit severe vacuolar demyelination of the spinal cord that result in age dependent degenerative phenotypes that recapitulate the salient features of ADLD. The late age of onset of the together with the relatively slow progression of the disease provides a large therapeutic window for the disorder. However, no treatment exits for ADLD, representing an urgent and unmet clinical need. This proposal aims to test the hypothesis that reducing lamin B1 levels can delay or reverse the progression of the disease in a a novel mouse model we have generated where the overexpression of Lamin B1 can be inducibly downregulated. We propose to fully characterize this mouse model and downregulate overexpression at time points before and after the onset of disease to determine if this will mitigate the pathological phenotype. These experiments will provide the first clear evidence that reducing Lamin B1 levels is a viable therapeutic strategy in an ADLD pre-clinical model.

抽象的 常染色体显性脑白质营养不良 (ADLD) 是一种致命的、进行性成人发病的疾病，其特征是 自主神经和运动功能障碍，伴有广泛的中枢神经系统脱髓鞘。我们之前已经证明 ADLD 是 由核纤层蛋白 B1 基因重复引起，核纤层蛋白 B1 表达增加是该疾病的基础 过程。在真核细胞中，核纤层蛋白 B1 是核纤层的主要成分，核纤层是邻近核纤层的纤维网状结构。 到内核​​膜。我们已经证明，具有少突胶质细胞特异性的转基因（TG）小鼠 核纤层蛋白 B1 的过度表达表现出严重的脊髓空泡脱髓鞘，导致年龄依赖性 退化表型概括了 ADLD 的显着特征。 发病年龄较晚，加上疾病进展相对缓慢，为患者提供了很大的帮助。 该疾病的治疗窗口。然而，ADLD 尚无治疗方法，这是一个紧迫且未得到满足的问题 临床需要。该提案旨在检验以下假设：降低核纤层蛋白 B1 水平可以延迟或逆转 我们建立了一种新的小鼠模型，其中 Lamin B1 过度表达，该疾病的进展 可以诱导下调。我们建议充分表征该小鼠模型并下调 在疾病发作之前和之后的时间点过度表达，以确定这是否会减轻 病理表型。这些实验将提供第一个明确的证据，证明降低核纤层蛋白 B1 水平是 ADLD 临床前模型中可行的治疗策略。