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. The nuclear lamina maintains the structural integrity of the nucleus and has roles in essential cellular processes including transcription, DNA replication, DNA repair, and epigenetic regulation. We have recently 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 reminiscent of ADLD. 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. This proposal aims to test the potential of antisense oligonucleotides (ASOs) to delay or reverse the progression of the disease in a mouse model of ADLD. ASOs are synthetic single stranded nucleic acids with a modified backbone that bind to RNA and thereby reduce expression of the target RNA or alter protein expression through interference of pre-mRNA splicing. Their mechanism of actions thus makes them ideally suited for a disease such as ADLD that is caused by an overexpression of a protein. ASOs also have tremendous translational potential and some of these molecules have demonstrated efficacy in clinical trials for neurological disorders such as spinal muscular atrophy (SMA).
Autosomal dominant leukodystrophy (ADLD) is an adult onset disease which leads to CNS degeneration resulting in muscle wasting, weakness and early death for which there is no treatment. We propose to test a class of molecules called antisense oligonucleotides (ASOs) in a mouse model of ADLD to reduce the production of the causative protein, lamin B1, to determine whether it can delay or reverse the disease phenotype.
