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

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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.