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

摘要 常染色体显性遗传性脑白质营养不良(ADLD)是一种致命的进行性成人发病疾病，其特征是 自主神经和运动功能障碍伴广泛的中枢神经系统脱髓鞘。我们之前已经证明，ADLD是 由lamin b1基因重复引起，lamin b1表达增加是该病的基础 进程。在真核细胞中，层蛋白B1是核层的主要组成部分，核层是相邻的纤维网 到内核膜。我们已经证明，转基因(TG)小鼠具有少突胶质细胞特异性 层蛋白B1的过度表达显示脊髓严重的空泡脱髓鞘，导致年龄依赖性 退化表型概括了ADLD的显著特征。 发病年龄较晚，加上疾病进展相对缓慢，提供了很大的 治疗这种疾病的窗口。然而，对于ADLD没有治疗，这代表着一个紧急和未得到满足的 临床需要。这项提议旨在检验这样一种假设，即降低Lamin B1水平可以延迟或逆转 在我们建立的一种新的小鼠模型中疾病的进展，其中Lamin B1的过度表达 可以被诱导地下调。我们建议充分描述这一小鼠模型，并下调 在发病前后的时间点过度表达，以确定这是否会缓解 病理表型。这些实验将提供第一个明确的证据，表明降低Lamin B1水平 ADLD临床前模型中的可行治疗策略。

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.