Autosomal dominant leukodystrophy (ADLD) is a fatal, progressive adult-onset disease characterized by widespread CNS demyelination and significant morbidity. The late age of onset 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. We have previously shown that ADLD is caused by duplications of the lamin B1 gene causing increased expression of the lamin B1 protein. In eukaryotic cells, lamin B1 is a major constituent of the nuclear lamina, a fibrous meshwork adjacent to the inner nuclear membrane. The nuclear lamina maintains the structural integrity of the nucleus and has essential roles in multiple cellular processes. We have recently demonstrated that transgenic mice with oligodendrocyte-specific over-expression of lamin B1 exhibit temporal and histo-pathological features reminiscent of the human disease. ADLD patient fibroblasts and mouse embryonic fibroblasts (MEFs) that we have engineered to overexpress lamin B1, manifest distinct and quantifiable nuclear abnormalities. As an increased level of lamin B1 is the causative agent triggering ADLD, approaches aimed at reducing lamin B1 levels and associated functional consequences represent a potent and innovative strategy for discovery of small molecule ADLD therapeutics. We have developed high-content analysis to define, analyze, and quantify the abnormal nuclear phenotype caused by lamin B1 overexpression. Preliminary assay performance suggests that the assay can satisfy HTS criteria. In three specific aims we will 1) optimize the HCS assay to accepted screening criteria; 2) perform a large scale HTS using the NIH Molecular Libraries Small Molecule Repository (MLSMR) maintained by University of Pittsburgh Drug Discovery Institute (UPDDI); and 3) credential positives for downregulation of lamin B1 in ADLD patient fibroblasts and for effects on the expression of functionally relevant lipid modifying genes in oligodendrocytes from lamin B1 overexpressing mice. As the discovery paradigm is based on a defined genetic mutation, clinical observations, and disease-relevant models, we expect to identify bona fide correctors of lamin B1 pathophysiology as candidates for development into potential therapies for ADLD in preclinical mouse models and clinical trials in patients.

Public Health Relevance

Autosomal dominant leukodystrophy (ADLD) is a debilitating neurodegenerative disease that occurs later in life, results in early death, and for which no treatments exist. The root cause for ADLD is overproduction of a protein called lamin B1 in the central nervous system, which leads to demyelination. Myelin is the fatty substance that insulates and protects nerves. This project aims to discover novel agents that reduce lamin B1 levels and correct the myelin defect.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants Phase II (R33)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Roof, Rebecca
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code